Dihydroindolone compounds, a process for their preparation and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula (I): 
                         
wherein:
         m and n represent 1 or 2,   A represents a pyrrolyl group,   X represents a C(O), S(O) or SO 2  group,   R 1  and R 2  represent an alkyl group   or, together with the nitrogen atom carrying them, form a heterocyclic group,   R 3  and R 4 , together with the atoms carrying them, form a heterocyclic group,   R 5  represents a hydrogen atom or an alkyl group,   R 6  represents a hydrogen atom or a halogen atom.       

     Medicinal products containing the same which are useful in treating cancer.

The present invention relates to new dihydroindolone compounds, to aprocess for their preparation and to pharmaceutical compositionscontaining them.

The compounds of the present invention are new and have very valuablepharmacological characteristics in the field of oncology.

The demands of anticancer therapy require the constant development ofnew antitumour agents with the aim of obtaining medicaments that aresimultaneously more active and better tolerated.

One of the major problems in oncology comes from the ability ofcancerous cells to migrate to other sites from the primary tumourformed. Cell migration is a physiological process that is crucial forembryonic development and the maintenance of tissue homeostasis.Migration causes substantial morphological changes to come about andinvolves repression of intracellular signalling pathways.

Deregulation of cell migration is highly involved in cancer pathology,and more especially in the process of the formation of metastases(Hanahan D. et al., 2000, Cell, 100, 57-70). It is accordinglyespecially important to be able to control this process, whichinevitably leads to generalised cancer and certain death of the patient.

Besides being new, the compounds of the present invention havesurprising in vitro activity in inhibiting the migration of cancerouscells and, accordingly, tumour progression. The compounds of the presentinvention accordingly have properties which make them especially usefulfor the treatment of cancers and, especially, metastatic solid tumours.

The present invention relates more especially to compounds of formula(I):

wherein:

-   -   m represents 1 or 2,    -   n represents 1 or 2,    -   A represents a pyrrolyl group which is unsubstituted or        substituted by 1 to 3 linear or branched (C₁-C₆)alkyl groups,    -   X represents a C(O), S(O) or SO₂ group,    -   R₁ and R₂, which are the same or different, each represent a        linear or branched (C₁-C₆)alkyl group,    -   or R₁ and R₂, together with the nitrogen atom carrying them,        form a heterocyclic group,    -   R₃ and R₄, together with the atoms carrying them, form a        heterocyclic group,    -   R₅ represents a hydrogen atom or a linear or branched        (C₁-C₆)alkyl group,    -   R₆ represents a hydrogen atom or a halogen atom,        it being understood that:    -   a “heterocyclic group” means a mono- or bi-cyclic group which        may contain from 5 to 8 apices, which may contain from one to        three hetero atoms selected from nitrogen, oxygen and sulphur,        and which may contain one or more unsaturated bonds, it being        possible for the heterocyclic group so defined to be        unsubstituted or substituted by one or more groups selected from        linear or branched (C₁-C₆)alkyl, linear or branched        (C₁-C₆)alkenyl, oxo, hydroxy, linear or branched (C₁-C₆)alkoxy,        aryl, arylalkyl and arylalkenyl,    -   “aryl” means a phenyl group which is unsubstituted or        substituted by one or more groups selected from halogen atoms        and linear or branched (C₁-C₆)alkyl groups,    -   the notation        means that the double bond is of configuration Z or E,        to their optical and geometric isomers, and also to addition        salts thereof with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric acid, hydrobromic acid,sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,oxalic acid, methanesulphonic acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned,without implying any limitation, sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine etc.

Preference is given to the value of n and of m being 1.

R₁ and R₂ advantageously represent an alkyl group such as, for example,an ethyl group or, together with the nitrogen atom carrying them, form a5- or 6-membered monocyclic group such as, for example, a piperidyl,morpholinyl, pyrrolidinyl, piperazinyl or methylpiperazinyl group or abicyclic group having from 6 to 8 members such as, for example, anoctahydrocyclopentapyrrolyl or azabicyclo[3.1.0]hexanyl group.Preferably, R₁ and R₂, together with the nitrogen atom carrying them,form a morpholinyl group.

Advantageously, R₃ and R₄, together with the X group and the nitrogenatom carrying them, form a 5- or 6-membered monocyclic group such as,for example, a pyrrolidinonyl, pyrrolidinedionyl, oxazolidinonyl,oxazolidinedionyl, dimethyloxazolidinedionyl, thiazolidinonyl,thiazolidinedionyl, dimethylthiazolidinedionyl, imidazolidinonyl,imidazolidinedionyl, thiadiazinonyl or dihydrothiadiazinonyl group or a6-membered bicyclic group such as, for example, anazabicyclo[3.1.0]hexanonyl or azabicyclo[3.1.0]hexanedionyl group.Preference is given to R₃ and R₄, together with the X group and thenitrogen atom carrying them, forming a 2,4-dioxo-1,3-thiazolidin-3-yl,2,4-dioxo-1,3-oxazolidin-3-yl, 2-oxo-1,3-thiazolidin-3-yl,2-oxo-1,3-oxazolidin-3-yl, 4-hydroxy-2-oxo-1,3-thiazolidin-3-yl or2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl group.

R₅ advantageously represents a hydrogen atom or a methyl or ethyl group.

X preferably represents a C(O) group.

Preference is given to A being an unsubstituted pyrrolyl group and, moreespecially, a 1H-pyrrol-2,4-yl group.

The invention relates preferably to compounds of formula (I) wherein R₁and R₂, together with the nitrogen atom carrying them, form amorpholinyl group, m and n have the value 1, R₅ and R₆ represent ahydrogen atom and A represents a 1H-pyrrol-2,4-yl group.

The exocyclic double bond of the compounds of formula (I) is ofconfiguration Z or E, more especially of configuration Z.

Even more especially, the invention relates to compounds of formula (I)which are:

-   3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione,-   3-[3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-oxazolidine-2,4-dione,-   3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-yl-methyl)-1,3-dihydro-indol-2-one,-   5-(4-hydroxy-2-oxo-thiazolidin-3-ylmethyl)-3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one,-   (1R,5S)-3-[3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-3-aza-bicyclo[3.1.0]hexane-2,4-dione,-   3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-thiazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one,-   3-{3-[1-(4-morpholin-4-ylmethyl-1H-pyrrol-2-yl)-propylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl}-thiazolidine-2,4-dione,-   3-{3-[1-(4-morpholin-4-ylmethyl-1H-pyrrol-2-yl)-ethylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl}-thiazolidine-2,4-dione.

The optical and geometric isomers of preferred compounds of theinvention, and also addition salts thereof with a pharmaceuticallyacceptable acid or base, form an integral part of the invention.

The invention relates also to a process for the preparation of compoundsof formula (I), which process is characterised in that there is used asstarting material the compound of formula (II):

wherein n and R₆ are as defined for formula (I),with which there is condensed, in the presence of a base, the compoundof formula (III):

wherein X, R₃ and R₄ are as defined for formula (I),to yield the compound of formula (IV):

wherein n, X, R₃, R₄ and R₆ are as defined hereinbefore,which is subjected to chemical or catalytic hydrogenation to yield thecompound of formula (V):

wherein n, X, R₃, R₄ and R₆ are as defined hereinbefore,which is subjected to the action of tBuOCl in the presence of ethyl(methylsulphanyl)acetate, followed by the successive action oftriethylamine and of hydrochloric acid, to yield the compound of formula(VI):

wherein n, X, R₃, R₄ and R₆ are as defined hereinbefore,which is subjected to the action of powdered zinc to yield the compoundof formula (VII):

wherein n, X, R₃, R₄ and R₆ are as defined hereinbefore,with which there is condensed, in the presence of piperidine, thecompound of formula (VIII):

wherein m, A, R₁, R₂, and R₅ are as defined for formula (I),to yield, after acid treatment, the compound of formula (I), which maybe purified according to a customary separation technique, converted, ifdesired, into its addition salts with a pharmaceutically acceptable acidor base and separated, where appropriate, into its isomers according toa customary separation technique.

The compounds of formulae (II), (III) and (VIII) are either commerciallyavailable or accessible to the person skilled in the art by means ofcustomary chemical reactions or chemical reactions described in theliterature.

An advantageous variant relates to a process for the preparation ofcompounds of formula (I), which process is characterised in that thereis used as starting material the compound of formula (IX):

wherein n′ represents 0 or 1, and R represents a linear or branched(C₁-C₆)alkyl group, and R₆ is as defined for formula (I),which is subjected to the action of tBuOCl in the presence of ethyl(methylsulphanyl)acetate, followed by the successive action oftriethylamine and of hydrochloric acid, to yield the compound of formula(X):

wherein n′, R and R₆ are as defined hereinbefore,which is subjected to the action of powdered zinc to yield the compoundof formula (XI):

wherein n′, R and R₆ are as defined hereinbefore,which is placed in a reducing medium to yield the compound of formula(XII):

wherein n and R₆ are as defined hereinbefore,with which there is condensed, in the presence of piperidine, thecompound of formula (VIII):

wherein m, A, R₁, R₂, and R₅ are as defined for formula (I),to yield, after acid treatment, the compound of formula (XIII):

wherein m, n, A, R₁, R₂, R₅ and R₆ are as defined hereinbefore,with which there is condensed directly in the presence oftriphenylphosphine and, for example, ethyl azodicarboxylate the compoundof formula (III):

wherein X, R₃ and R₄ are as defined for formula (I),to yield the compound of formula (I), which may be purified according toa customary separation technique, converted, if desired, into itsaddition salts with a pharmaceutically acceptable acid or base andseparated, where appropriate, into its isomers according to a customaryseparation technique.

The compounds of formulae (III), (VIII) and (IX) are either commerciallyavailable or accessible to the person skilled in the art by means ofcustomary chemical reactions or chemical reactions described in theliterature.

Pharmacological study of the compounds of the invention has shown themto have the ability to inhibit the migration of cancerous cells. Thisproperty therefore is of major therapeutic value in the treatment ofcancers, more especially in the treatment of metastatic cancers.

Among the envisaged cancer treatments there may be mentioned, withoutbeing limited thereto, cancers of the colon, breast, liver, kidneys,brain, oesophagus, melanomas, myelomas, cancers of the ovary, non-smallcell lung cancers, small cell lung cancers, cancers of the prostate andpancreas, and sarcomas.

The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I) on its own or incombination with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention theremay be mentioned more especially those that are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration, and especially tablets or dragées,sublingual tablets, sachets, paquets, capsules, glossettes, lozenges,suppositories, creams, ointments, dermal gels and drinkable orinjectable ampoules.

The useful dosage varies according to the sex, age and weight of thepatient, the administration route, the nature of the therapeuticindication and any associated treatments and ranges from 0.01 mg to 1 gper 24 hours in 1 or more administrations.

The present invention moreover relates also to the association of acompound of formula (I) with an anticancer agent selected from genotoxicagents, mitotic poisons, antimetabolites, proteasome inhibitors andkinase inhibitors and also to the use of this type of association in themanufacture of medicaments for use in the treatment of cancer.

The compounds of the invention may also be used in association withradiotherapy in the treatment of cancer.

The Preparations and Examples that follow illustrate the inventionwithout limiting it in any way.

The melting points are measured in a capillary apparatus.

PREPARATION 1 4-Morpholin-4-ylmeth 1-1H-pyrrole-2-carbaldehyde

To a solution of morpholine (0.38 mole) in acetic acid (120 ml) at 0° C.there is added a solution of 1H-pyrrole-2-carbaldehyde (0.32 mole) inacetic acid (100 ml). Formaldehyde (37% aq., 26 ml) is then addeddropwise. The reaction mixture is then stirred for 65 hours at ambienttemperature. The mixture is concentrated (about 50 ml) and cooled in anice bath. The pH of the solution is made alkaline (pH=12) using 20%aqueous sodium hydroxide solution. The product is extracted withdichloromethane (DCM) (3×250 ml). The organic phases are combined. Theorganic phase obtained is washed with saturated aqueous NaCl solution,dried over sodium sulphate, filtered and evaporated to dryness. Theresidue obtained (oil) is purified on silica gel (SiO₂, gradientDCM/MeOH) to yield the title product.

Mass spectrometry (ES+, m/z): 195.1124 (M+H)⁺

PREPARATION 2 1-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-yl)-ethanone

To a solution of morpholine (22 mmoles) in acetic acid (60 ml) at 0° C.there are added 1-(1H-pyrrol-2-yl)-ethanone (20 mmoles) and formaldehyde(20 mmoles) 37% in water. The reaction mixture is stirred overnight atambient temperature. At 0° C., the solution is brought to alkaline pH(10-12) using 20% aqueous NaOH solution and is then extracted with DCM.The organic phase is washed with water and with saturated aqueous NaClsolution, dried over sodium sulphate, filtered and evaporated todryness. Purification by flash chromatography on silica gel (SiO₂;gradient DCM/MeOH) to yield the title product.

Mass spectrometry (ES+, m/z): 209.1289 (M+H)⁺

PREPARATION 34-[(1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde

To a solution of (1R,5S)-3-aza-bicyclo[3.1.0]hexane (10 mmoles) inacetic acid (10 ml) there are added 10 mmoles of3,5-dimethyl-1H-pyrrole-2-carbaldehyde and formaldehyde (11 mmoles) 37%in water. The reaction mixture is stirred overnight at ambienttemperature and then evaporated to dryness. Purification by flashchromatography on silica gel (SiO₂; heptane/AcOEt) and then triturationin heptane to yield the title product.

Mass spectrometry (ES+, m/z): 219.1503 (M+H)⁺

PREPARATION 44-((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 1, replacing the morpholine by(1R,5S)-3-azabicyclo-[3.1.0]hexane.

Mass spectrometry, (ES+, m/z): 191.1179 (M+H)⁺

PREPARATION 5 1-(4-Morpholin-4-ylmethyl-4H-pyrrol-2-yl)-propan-1-one

To a solution of morpholine (89.3 mmoles) in acetic acid (50 ml) at 0°C. there are added 1-(1H-pyrrol-2-yl)-propan-1-one (81.2 mmoles) andformaldehyde (89.3 mmoles) 37% in water. The reaction mixture is stirredovernight at ambient temperature. After concentration of the mixture,the solution is brought to alkaline pH (10-12) using 20% aqueous NaOHsolution at 0° C. and is then extracted with DCM. The organic phase iswashed with water and with saturated aqueous NaCl solution, dried oversodium sulphate, filtered and evaporated to dryness and purified byflash chromatography on silica gel (SiO₂; gradient 100% AcOEt toAcOEt/MeOH 9/1) to yield the title product.

Mass spectrometry (ES+, m/z): 223.1444 (M+H)⁺

PREPARATION 6 1-Methyl-4-morpholin-4-ylmethyl-4H-pyrrole-2-carbaldehydeand 1-methyl-5-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde

To a solution of morpholine (130 mmoles) in acetic acid (60 ml) at 0° C.there are added 1-methyl-1H-pyrrole-2-carbaldehyde (110 mmoles) andformaldehyde (110 mmoles) 37% in water. The reaction mixture is stirredfor 16 hours at 50° C. After evaporation to dryness, about 100 ml of 25%aqueous sodium hydroxide solution are added. After extraction with DCM,the organic phase is washed with water and with saturated aqueous NaClsolution, dried over sodium sulphate, filtered and evaporated todryness. The residue is purified by flash chromatography on silica gel(SiO₂; gradient AcOEt/MeOH) to yield the title products1-methyl-4-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde and1-methyl-5-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde in a ratio of1/5.

1-Methyl-4-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde

Mass spectrometry, (ES+, m/z): 209.1282 (M+H)⁺

1-Methyl-5-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde

Mass spectrometry, (ES+, m/z): 209.1286 (M+H)⁺

PREPARATION 7 5-Morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde Step A:4-(1H-Pyrrol-2-ylmethyl)-morpholine

To a solution of morpholine (22 mmoles) in acetic acid (10 ml) there isadded pyrrole (20 mmoles) dropwise at 0° C. Formaldehyde (37% aq., 20mmoles) is then added dropwise. The reaction mixture is stirred for 2hours at ambient temperature. The solution is cooled to 0° C. and isbrought to alkaline pH (10-11) using 20% aqueous NaOH solution. Afterextraction with DCM, the organic phases are washed with water and withsaturated aqueous NaCl solution, dried over sodium sulphate, filteredand evaporated to dryness to yield the title product in the form of awhite solid which is used directly in the next Step.

Step B: 5-Morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde

To a solution of DMF (18.04 mmoles) in DCM (10 ml) there is added POCl₃,dropwise, at 0° C. After stirring for 5 minutes, a solution of thecompound obtained in Step A (9.02 mmoles) is added dropwise. Afterstiffing for 3 hours at 0° C., the reaction mixture is heated at 40° C.for 30 minutes. At ambient temperature, an aqueous solution of potassiumacetate (32 mmoles) is added and then the reaction mixture is stirred at40° C. for 30 minutes. At ambient temperature, the solution is broughtto alkaline pH using 2M NaOH solution and is then extracted with DCM.The organic phase is washed with water and with saturated NaCl solution,dried over sodium sulphate, filtered and evaporated to dryness. Theresidue obtained is purified on silica gel (SiO₂; gradient DCM/AcOEt) toyield the title product.

Mass spectrometry (ES+, m/z): 195.1150 (M+H)⁺

PREPARATION 8 3-Morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde Step A:4-(1-Triisopropylsilanyl-1H-pyrrol-3-ylmethyl)-morpholine

To a solution of morpholine (98.5 mmoles) in acetic acid (100 ml) at 0°C. there are added 1-triisopropylsilanyl-1H-pyrrole (89.5 mmoles) andformaldehyde (89.5 mmoles) 37% in water. The reaction mixture is stirredovernight at ambient temperature. The solution is brought to alkaline pH(10-12) using 20% aqueous NaOH solution and is then extracted with DCM.The organic phase is washed with water and with saturated aqueous NaClsolution, dried over sodium sulphate, filtered and evaporated todryness. The residue obtained is purified by flash chromatography onsilica gel (SiO₂; gradient DCM/AcOEt) to yield the title product, whichis used directly in the next Step.

Step B: 4-(1H-Pyrrol-3-ylmethyl)-morpholine

To a solution of the compound obtained in Step A (75 mmoles) in THF (100ml) there is added, dropwise, at 0° C., Bu₄NF 1.0M in THF (75.0 mmoles).After stiffing at 0° C. for one hour, the solution is poured onto iceand is then extracted with DCM. The organic phases are combined and thenwashed with saturated aqueous NaCl solution, dried over sodium sulphate,filtered and evaporated to dryness to yield the title product, which isused directly in the next Step.

Step C: 3-Morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde

To a solution of DMF (66 mmoles) in DCM there is added, dropwise, at 0°C., POCl₃. After stirring for 5 minutes, a solution of the compoundobtained in Step B (33 mmoles) in DCM (60 ml) is added dropwise. Afterstiffing for 4 hours at 0° C. and for 30 minutes at reflux, an aqueoussolution of sodium acetate (110 mmoles) is added. After a further 30minutes at reflux, aqueous 2M sodium hydroxide solution is added atambient temperature until the pH is alkaline (9-10). The solution isstirred for 2 hours at ambient temperature, and then 300 ml of DCM areadded. After extracting with DCM, the organic phase is washed with waterand with saturated aqueous NaCl solution, dried over sodium sulphate,filtered and evaporated to dryness. The residue obtained is purified byflash chromatography on silica gel (SiO₂; gradient DCM/AcOEt) to yieldthe title product.

Mass spectrometry (ES+, m/z): 195.1134 (M+H)⁺

PREPARATION 9 5-Diethylaminomethyl-1,1-pyrrole-2-carbaldehyde

The procedure is as in Preparation 7, replacing the morpholine bydiethylamine.

Mass spectrometry (ES+, m/z): 181.1340 (M+H)⁺

PREPARATION 104-(4-Methyl-piperazin-1-ylmethyl)-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 1, replacing the morpholine by1-methyl-piperazine.

Mass spectrometry (ES+, m/z): 208.1436 (M+H)⁺

PREPARATION 11 4-Pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 1, replacing the morpholine bypyrrolidine.

Mass spectrometry (ES+, m/z): 179.1183 (M+H)⁺

PREPARATION 12 4-((3aR,6aS)-Hexahydro-cyclopenta[c]pyrrol-2-(1H)-ylmethyl)-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 1, replacing the morpholine by(3aR,6aS)-hexahydro-cyclopenta[c]pyrrole.

Mass spectrometry, (ES+, m/z): 219.1481 (M+H)⁺

PREPARATION 13 4-Piperidin-1-ylmethyl-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 1, replacing the morpholine by(3aR,6aS)-hexahydro-cyclopenta[c]pyrrole.

Mass spectrometry (ES+, m/z): 193.1349 (M+H)⁺

PREPARATION 14 4-Diethylaminomethyl-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 1, replacing the morpholine bydiethylamine.

Mass spectrometry (ES+, m/z): 181.1342 (M+H)⁺

PREPARATION 154-((3aR,6aS)-Hexahydro-cyclopenta[c]pyrrol-2(1H)-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 3, replacing the(1R,5S)-3-azabicyclo[3.1.0]hexane by(3aR,6aS)-hexahydro-cyclopenta[c]pyrrole.

Mass spectrometry (ES+, m/z): 247.1785 (M+H)⁺

PREPARATION 16 5-Morpholin-4-ylmethyl-1H-pyrrole-3-carbaldehyde

The procedure is as in Preparation 1, replacing the1H-pyrrole-2-carbaldehyde by 1H-pyrrole-3-carbaldehyde.

Mass spectrometry, (ES+, m/z): 195.1133 (M+H)⁺

PREPARATION 175-((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrole-3-carbaldehyde

The procedure is as in Preparation 1, replacing the1H-pyrrole-2-carbaldehyde by 1H-pyrrole-3-carbaldehyde and replacing themorpholine by (1R,5S)-3-azabicyclo-[3.1.0]hexane.

Mass spectrometry (ES+, m/z): 191.1175 (M+H)⁺

PREPARATION 18 4-[2-(Pyrrolidin-1-yl)ethyl]-1H-pyrrole-2-carbaldehydeStep A: 2,2,2-Trichloro-1-(1H-pyrrol-2-yl)ethanone

To a solution of trichloroacetyl chloride (160.7 mmoles) in ethyl ether(26 ml) there is added, dropwise over a period of 3 hours, a solution ofpyrrole (149 mmoles) in ethyl ether (83 ml). After stirring for afurther hour, a solution of potassium carbonate (94 mmoles) in water (39ml) is added dropwise. The phases are separated and the organic phase isdried over sodium sulphate and filtered. Active carbon is added to thisorganic phase. After stirring for 5 minutes, the organic phase isfiltered and evaporated to dryness to yield the title product.

Step B: 5-(Trichloroacetyl)-1H-pyrrole-3-carbaldehyde

To a solution of the compound obtained in Step A (87 mmoles) and AlCl₃in a DCM/nitromethane mixture (80 ml/80 ml) there is added, dropwise, at−30° C., dichloro-methoxy-methane (130.5 mmoles). After stiffing for twohours, the reaction mixture is poured into 800 ml of ice-cold water. Theaqueous phase is extracted with AcOEt, and then the organic phases arecombined. The organic phase is washed with saturated aqueous NaClsolution, dried over sodium sulphate, filtered and evaporated to drynessto yield the title product (brown crystals), which is used directly inthe next Step.

Step C: Ethyl 4-formyl-1H-pyrrole-2-carboxylate

To a solution of the compound obtained in Step B (83.7 mmoles) inethanol (200 ml) there is added, dropwise and over 20 minutes, asolution of sodium ethanolate (13.4 mmoles) in ethanol (45 ml) atambient temperature. After stirring for 3 hours, the mixture isevaporated to dryness and then taken up in ethyl ether (200 ml). To thatorganic phase there is added aqueous 2N HCl solution (150 ml) and theresulting mixture is stirred; the phases are then separated and theaqueous phase is extracted with ethyl ether. The organic phase is washedwith saturated aqueous NaHCO₃ solution and with saturated aqueous NaClsolution, dried over sodium sulphate, filtered and evaporated to drynessto yield the title product (brown crystals), which is used directly inthe next Step.

Step D: Ethyl 4-[(dimethylamino)methyl]-1H-pyrrole-2-carboxylate

To a solution of the compound obtained in Step C and dimethylamine (1.1eq.) there is added, in portions, NaBH(OAc)₃ (952 mg). The mixture isstirred overnight at ambient temperature. After evaporation to dryness,the residue is taken up in CH₂Cl₂ and water. The aqueous phase isextracted with CH₂Cl₂. The organic phases are combined and thenextracted with aqueous 1N HCl solution. The aqueous phase is madealkaline and is then extracted with CH₂Cl₂. The organic phase is driedover magnesium sulphate, filtered and evaporated to dryness to yield thetitle product, which is used directly in the next Step.

Step E:[5-(Ethoxycarbonyl)-1H-pyrrol-3-yl]-N,N,N-trimethyl-methanaminium iodide

To a solution of the product obtained in Step D (0.3 g) in a mixture oftetrahydrofuran (2.2 ml) and CH₂Cl₂ (2.2 ml) there is added methyliodide (0.350 ml). A precipitate appears. The reaction mixture isstirred for one hour at ambient temperature and is then left at 4° C.overnight. The reaction mixture is evaporated to dryness and the residueobtained is used directly in the next Step.

Step F: Ethyl 4-(cyanomethyl)-1H-pyrrole-2-carboxylate

A solution of the product obtained in Step E and sodium cyanide (0.225g) in ethanol is heated at reflux for 72 hours. After evaporation todryness, the residue is taken up in a mixture of CH₂Cl₂/water. Theaqueous phase is extracted three times with CH₂Cl₂. The organic phasesare combined. The organic phase is dried over magnesium sulphate,filtered and evaporated to dryness to yield the title product which isused directly in the next Step.

Step G: Ethyl 4-(2-aminoethyl)-1H-pyrrole-2-carboxylate

To a solution of the product obtained in Step F (7.45 g) in MeOH (1.5 L)there are added 223 ml of a 1.4N solution of NH₃ in MeOH and PtO₂ (5.2g). The reaction mixture is placed under an atmosphere of hydrogen andis then stirred for 20 hours at ambient temperature. After filtrationand evaporation to dryness, the residue obtained is purified on silicagel (SiO₂: gradient CH₂Cl₂/MeOH with the addition of 1.4N NH₃ in theMeOH) to yield the title product which is used directly in the nextStep.

Step H: Ethyl 4-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrrole-2-carboxylate

To a solution of the product obtained in Step G (1.3 g) in DMF (134 ml)there are added 2,6-lutidine (4.15 ml) and 1,4-dibromo-butane (4.68 ml).The reaction mixture is stirred at 80° C. for 12 hours and at ambienttemperature overnight. The reaction mixture is diluted with 600 ml ofethyl acetate. The organic phase is washed with saturated aqueous NaHCO₃solution, with water and with saturated aqueous NaCl solution, driedover magnesium sulphate, filtered and evaporated to dryness. The residueobtained is purified on silica gel (SiO₂: gradient CH₂Cl₂/MeOH with theaddition of 1.4N NH₃ in the MeOH) to yield the title product, which isused directly in the next Step.

Step I: {4-[2-(Pyrrolidin-1-yl)ethyl]-1H-pyrrol-2-yl}methanol

To a solution of the product obtained in Step H (0.2 g) in THF (10 ml)at 0° C. there is added, in portions, lithium aluminium hydride. Afterstiffing for 3 hours at ambient temperature, the reaction mixture ishydrolysed at 0° C. with aq. NaOH solution and water. After filtration,the filtrate is evaporated to dryness and the residue obtained ispurified on silica gel (SiO₂: gradient CH₂Cl₂/MeOH with the addition of1.4N NH₃ in the MeOH) to yield the title product, which is used directlyin the next Step.

Step J: 4-[2-(Pyrrolidin-1-yl)ethyl]-1H-pyrrole-2-carbaldehyde

To a solution of the product obtained in Step I (0.09 g) in THF (3.8 ml)there is added activated MnO₂ (0.315 g). After stirring for 20 hours atambient temperature, the mixture is filtered and the filtrate isevaporated to dryness to yield the title product, which is used directlyin the next step.

PREPARATION 19 4-[2-(Morpholin-4-yl)ethyl]-1H-pyrrole-2-carbaldehyde

The title product is obtained as described in Preparation 18, replacingthe 1,4-dibromo-butane in Step H by 1-bromo-2-(2-bromoethoxy)ethane.

PREPARATION 205-[(3aR,6aS)-Hexahydrocyclopenta[c]pyrrol-2(1H)-ylmethyl]-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 1, replacing the morpholine by(3aR,6aS)-hexahydro-cyclopenta[c]pyrrole.

Mass spectrometry, (ES+, m/z): 219.1494 (M+H)

PREPARATION 214-[(4-Methoxypiperidin-1-yl)methyl]-1H-pyrrole-2-carbaldehyde

The procedure is as in Preparation 1, replacing the morpholine by4-methoxy-piperidine.

PREPARATION 22 4-(Morpholin-4′-ylmethyl)-1H-pyrrole-3-carbaldehyde StepA: Methyl 4-(morpholin-4-ylcarbonyl)-1H-pyrrole-3-carboxylate

To a solution of 4-(methoxycarbonyl)-1H-pyrrole-3-carboxylic acid (2.35g) in DMF (49 ml) there are added diisopropylethylamine (2.11 ml) andHATU (4.9 ml). After stiffing for 15 minutes at 40° C., morpholine (1.35ml) is added. After stiffing for 9 hours at 60° C. and at ambienttemperature over a weekend, the mixture is diluted with CH₂Cl₂ and 1Nsodium hydroxide solution. The aqueous phase is extracted 3 times withCH₂Cl₂ and the organic phases are combined. The organic phase is driedover magnesium sulphate, filtered and evaporated to dryness to yield thetitle product, which is used directly in the next Step.

Step B: [4-(Morpholin-4′-ylmethyl)-1H-pyrrol-3-yl]methanol

The title product is obtained using the protocol described in Step I ofPreparation 18 and starting from the product obtained in Step A.

Step C: 4-Morpholin-4-ylmethyl-1H-pyrrole-3-carbaldehyde

The title product is obtained using the protocol described in Step J ofPreparation 18 and starting from the product obtained in Step B.

By proceeding in the same manner as in Preparation 1, starting fromappropriate reagents, the following Preparation is obtained:

PREPARATION 234-[(2-Methyl-4-morpholinyl)methyl]-1H-pyrrole-2-carbaldehyde EXAMPLE 13-[(3-{[4-Morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dionehydrochloride Step A: Ethyl3-methylsulphanyl-2-oxo-2,3-dihydro-1H-indole-5-carboxylate

To a solution of ethyl 4-amino-benzoate (40.0 g) in DCM (900 ml) at −60°C. there is added, dropwise, ethyl (methylsulphanyl)acetate (34.5 ml)under a nitrogen atmosphere. 29.0 g of tBuOCl are then added, dropwise,to the reaction mixture over 25 minutes, maintaining the temperaturebetween −60° C. and −55° C. After stirring for one hour at −50° C.,triethylamine (15.4 ml) is added dropwise. The reaction mixture isbrought to 0° C. and then aqueous 3M HCl solution (485 ml) is addeddropwise. After stirring for 12 hours at ambient temperature, the phasesare separated and the organic phase is washed successively with aq. 2MHCl solution, water and then sat. aqueous NaCl solution. The organicphase is dried over sodium sulphate, filtered and evaporated to dryness.The residue obtained is taken up in ether. The crystals obtained arefiltered off, washed with ether and dried in vacuo to yield the titleproduct, which is used directly in the next Step.

Step B: Ethyl 2-oxo-2,3-dihydro-1H-indole-5-carboxylate

To a solution of the compound obtained in Step A (0.1448 mol) in glacialacetic acid (700 ml) there is added powdered zinc (0.8690 mol). Thetwo-phase mixture is stirred at 40° C. for 8 hours. The reaction mixtureis filtered and the filtrate is then evaporated to dryness. The residueis stirred in water overnight and filtered and the precipitate obtainedis washed with water. The product is taken up in toluene and thenevaporated to dryness, and is then taken up in ether, filtered, washedwith ether and then dried in vacuo at 40° C. under P₂O₅ to yield thetitle product, which is used directly in the next Step.

Step C: 5-Hydroxymethyl-1,3-dihydro-indol-2-one

To a solution/suspension of the compound obtained in Step B (66.8 mmol)in THF (850 ml) at −65° C. there is added, dropwise, 1M DIBAL-H solution(546 mmol) over one hour and under an inert atmosphere. The reactionmixture is brought to −30° C. over 1 hour 30 minutes. 22 ml of water areadded dropwise and then 22 ml of 15% aqueous sodium hydroxide solutionat 0° C. and then 55 ml of water. MgSO₄ (300 g) is added to the reactionmixture and stirring is carried out for 30 minutes. The suspension isfiltered over Celite and washed with THF. The filtrate is evaporated todryness to yield a pasty solid that is brown in colour. The residue istriturated in methanol, and the powder obtained is filtered off anddried in vacuo to yield the title product, which is used directly in thenext Step.

Step D:5-Hydroxymethyl-3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one

A solution of the compound obtained in Step C (18 mmol), and of thecompound obtained in Preparation 1 (19 mmol) and piperidine (18 mmol) inethanol is heated at reflux. After 40 minutes, the reaction mixture iscooled in an ice bath. The precipitate formed is filtered off and washedwith cold ethanol. The product obtained is taken up in toluene, heatedat reflux for 5 minutes and then evaporated to dryness and dried invacuo to yield the title product. Mixture of Z/E isomers (98/2)

Mass spectrometry (ES+, m/z): 340.1657 (M+H)⁺ and 340.1668 (M+H)⁺

Step E:3-[(3-{[4-(4-Morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dionehydrochloride

15.4 mmol of thiazolidine-2,4-dione and triphenylphosphine supported onresin (3 mmol/g, 30.8 mmol) are stirred under an inert atmosphere for 10minutes at ambient temperature in anhydrous THF. The mixture is cooledin an ice bath, and tert-butyl azodicarboxylate (15.4 mmol) is added.After stiffing for 10 minutes at 0° C., the compound obtained in Step D(10.2 mmol) is added. After stiffing for 1 hour 30 minutes at 0° C., themixture is filtered and the resin is washed with THF. The filtrate isevaporated to dryness and then chromatographed on silica. The productobtained is taken up in a mixture of DCM/methanol (4/1) (150 ml), andthen a 1.25M solution of HCl in ethanol (10 ml) is added. The solutionis concentrated to about 15 ml and is then cooled in an ice bath.

The crystals formed are filtered off under nitrogen, washed with coldethanol and dried in vacuo at 40° C. to yield the title product. Mixtureof Z/E isomers (99/1)

Mass spectrometry (ES+, m/z): 439.1439 (M+H)⁺ and 439.1431 (M+H)⁺

Melting point: 211° C.

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 55.63 4.88 11.80 6.75 7.46 Experimental %55.36 4.73 11.78 6.72 7.84

EXAMPLE 1A3-[(3-{[4-(4-Morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dionehydrochloride

The title compound is obtained by purification on silica gel (SiO₂;gradient CH₂Cl₂/MeOH) of the compound obtained in Step E of Example 1before conversion to a salt and then converting into the hydrochlorideas described in Step E of Example 1 to yield the title product. Mixtureof Z/E isomers (1.5/98.5)

Mass spectrometry (ES+, m/z): 439.1422 (M+H)⁺ and 439.1448 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 55.63 4.88 11.80 6.75 7.46 Experimental %56.06 4.81 11.84 6.99 7.48

EXAMPLE 1B3-[(3-{[4-(4-Morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione

15.4 mmol of thiazolidine-2,4-dione and triphenylphosphine supported onresin (3 mmol/g, 30.8 mmol) are stirred under an inert atmosphere for 10minutes at ambient temperature in anhydrous THF. The mixture is cooledin an ice bath, and tert-butyl azodicarboxylate (15.4 mmol) is added.After stiffing for 10 minutes at 0° C., the compound obtained in Step Dof Example 1 (10.2 mmol) is added. After stiffing for 1 hour 30 minutesat 0° C., the mixture is filtered and the resin is washed with THF. Thefiltrate is evaporated to dryness and then chromatographed on silica.

Mass spectrometry (ES+, m/z): 439.1435 (M+H)⁺

EXAMPLE 23-{3-[1-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-yl)-ethylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl}-thiazolidine-2,4-dionehydrochloride Step A:5-Hydroxymethyl-3-[1-(4-morpholin-4-ylmethyl-1H-pyrrol-2-yl)-ethylidene]-1,3-dihydro-indol-2-one

A solution of the compound obtained in Step C of Example 1 (2.5 mmoles),the compound obtained in Preparation 2 (2.9 mmoles) and ammonium acetate(5.2 mmoles) in ethanol (4 ml) is heated at 120° C. under microwaves for20 minutes. The precipitate obtained is filtered off, washed withethanol and ethyl ether and then dried in vacuo to yield the titleproduct. Mixture of Z/E isomers (99/1).

Mass spectrometry (ES+, m/z): 354.1799 (M+H)⁺ and 354.1793 (M+H)⁺

Step B:3-{3-[1-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-yl)-ethylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl}-thiazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the compound obtained in Step A (1.3mmoles) and thiazolidine-2,4-dione (1.7 mmoles). The product obtainedafter treatment is purified on silica gel (SiO₂; gradient AcOEt/MeOH)and then converted into the hydrochloride as described in Step E ofExample 1 to yield the title product. Mixture of Z/E isomers (99/1)

Mass spectrometry (ES+, m/z): 453.1586 (M+H)⁺ and 453.1600 (M+H)⁺

Melting point: 225° C.

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 56.49 5.15 11.46 6.56 7.25 Experimental %55.90 5.00 11.06 6.25 8.29

EXAMPLE 33-[3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-oxazolidine-2,4-dionehydrochloride Step A: Oxazolidine-2,4-dione

To a solution of NaOMe (1.05 mmoles) in MeOH (21 ml) there are added2-hydroxy-acetamide (1 mmole) and diethyl carbonate (1.15 mmoles), andthe reaction mixture is then heated at reflux for 1.5 hours. Thereaction mixture is evaporated to dryness and then taken up in water.The aqueous phase is extracted with diethyl ether. The aqueous phase isacidified (pH 2) and then evaporated to dryness. The residue istriturated in AcOEt and filtered. The product obtained is purified onsilica gel (c-Hexane/AcOEt; 1/1) to yield the title product in the formof a white powder.

Step B:3-[3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-oxazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the compound obtained in Step D ofExample 1 (4.8 mmol) and the compound obtained in Step A (7.31 mmol).The product obtained after filtration of the reaction mixture ispurified on silica gel (SiO₂; gradient AcOEt/MeOH) and is then convertedinto the hydrochloride as described in Step E of Example 1 to yield thetitle product. Mixture of Z/E isomers (97/3)

Mass spectrometry (ES+, m/z): 423.1670 (M+H)⁺ and 423.1697 (M+H)⁺

Melting point: 216° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 57.58 5.05 12.21 7.73 Experimental % 57.55 4.8012.21 7.96

EXAMPLE 43-{3-[1-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-yl)-ethylidene]-2-oxo-2,3-dihydro-4H-indol-5-ylmethyl}-oxazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the product obtained in Step A ofExample 2 (1.54 mmol) and the compound obtained in Step A of Example 3(2.31 mmol). The product obtained after treatment of the reactionmixture is purified on silica gel (SiO₂; gradient AcOEt to AcOEt/MeOH,9/1) and is then converted into the hydrochloride as described in Step Eof Example 1 to yield the title product. Mixture of Z/E isomers (99/1)

Mass spectrometry (ES+, m/z): 437.1816 (M+H)⁺ and 437.1837 (M+H)⁺

Melting point: 220° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 58.41 5.33 11.85 7.50 Experimental % 57.51 4.8412.07 8.51

EXAMPLE 53-{3-[4-1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-3,5-dimethyl-4H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-4H-indol-5-ylmethyl}-oxazolidine-2,4-dionehydrochloride Step A:3-[4-(1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-5-hydroxymethyl-1,3-dihydro-indol-2-one

The title product is obtained following the protocol described in Step Dof Example 1 by condensation of the compound obtained in Step C ofExample 1 (0.92 mmole) and the compound obtained in Preparation 3 (1mmole) in the presence of piperidine in ethanol at 105° C. undermicrowave activation. After filtration, the solid obtained is purifiedon silica gel (SiO₂; gradient AcOEt/MeOH) to yield the title product.Mixture of Z/E isomers (98/2)

Mass spectrometry, (ES+, m/z): 362.1875 (M−H)⁺ and 362.1883 (M−H)⁺

Step 13:3-{3-[4-(1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl}-oxazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the compound obtained in Step A (0.63mmole) and oxazolidine-2,4-dione (0.95 mmole). The product obtainedafter treatment of the reaction mixture is purified on silica gel (SiO₂;gradient AcOEt/MeOH) and is then converted into the hydrochloride asdescribed in Step E of Example 1 to yield the title product. Mixture ofZ/E isomers (99/1)

Mass spectrometry (ES+, m/z): 445.1865 (M−H)⁺ and 445.1846 (M−H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 62.17 5.63 11.60 7.34 Experimental % 61.98 6.2811.55 7.44

EXAMPLE 61-[3-(4-Morpholin-4-ylmethyl-1H-1-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-pyrrolidine-2,5-dionehydrochloride

The title product is obtained by following the protocol described inStep E of Example 1, replacing the thiazolidine-2,4-dione bypyrrolidine-2,5-dione. The product obtained after filtration of thereaction mixture is purified on silica gel (SiO₂; gradient AcOEt/MeOH)and is then converted into the hydrochloride as described in Step E ofExample 1 to yield the title product. Mixture of Z/E isomers (97/3)

Mass spectrometry (ES+, m/z): 421.1863 (M+H)⁺ and 421.1881 (M+H)⁺

Melting point: 212° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 60.46 5.51 12.26 7.76 Experimental % 60.75 5.3712.67 8.20

EXAMPLE 75,5-Dimethyl-3-[3-(4-morpholin-4-ylmethyl-4H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-oxazolidine-2,4-dionehydrochloride

The title product is obtained by following the protocol described inStep E of Example 1, replacing the thiazolidine-2,4-dione by5,5-dimethyl-oxazolidine-2,4-dione. The product obtained afterfiltration of the reaction mixture is purified on silica gel (SiO₂;gradient AcOEt/MeOH) and is then converted into the hydrochloride asdescribed in Step E of Example 1 to yield the title product. Mixture ofZ/E isomers (96/4)

Mass spectrometry (ES+, m/z): 451.1981 (M+H)⁺ and 451.1981 (M+H)⁺

Melting point: 191° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 59.20 5.59 11.51 7.28 Experimental % 59.37 5.4111.42 7.44

EXAMPLE 81-Methyl-3-[3-(4-morpholin-4-ylmethyl-4H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-4H-indol-5-ylmethyl]-imidazolidine-2,4-dionehydrochloride

The title product is obtained by following the protocol described inStep E of Example 1, replacing the thiazolidine-2,4-dione by1-methyl-imidazolidine-2,4-dione. The product obtained after filtrationof the reaction mixture is purified on silica gel (SiO₂; gradientAcOEt/MeOH) and is then converted into the hydrochloride as described inStep E of Example 1 to yield the title product. Mixture of Z/E isomers(97.5/2.5)

Mass spectrometry (ES+, m/z): 436.1981 (M+H)⁺ and 436.2001 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 58.54 5.55 14.84 7.51 Experimental % 57.74 5.2814.60 7.24

EXAMPLE 95-(4-Chloro-benzylidene)-3-[3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4′-dionehydrochloride Step A: 5-(4-Chloro-benzylidene)-thiazolidine-2,4-dione

A solution of 4-chloro-benzaldehyde (3 mmoles), thiazolidine-2,4-dione(3 mmoles) and piperidine (3 mmoles) in ethanol is heated at refluxovernight.

The reaction mixture is cooled in an ice bath. The crystals formed arefiltered off, washed with cold ethanol and dried in vacuo (40° C.) toyield the title product.

Mass spectrometry (ES+, m/z): 237.9732 (M−H)⁺

Step B:5-(4-Chloro-benzylidene)-3-[3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-yl-methylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4′-dionehydrochloride

The title product is obtained by following the protocol described inStep E of Example 1, replacing the thiazolidine-2,4-dione by thecompound obtained in Step A. The product obtained after filtration ofthe reaction mixture is purified on silica gel (SiO₂; gradientAcOEt/MeOH) and is then converted into the hydrochloride as described inStep E of Example 1 to yield the title product. Mixture of Z/E isomers(98.5/1.5)

Mass spectrometry (ES+, m/z): 561.1377 (M+H)⁺ and 561.1383 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 58.29 4.39 9.38 5.37 7.51 Experimental % 57.794.30 9.25 5.19 7.24

EXAMPLE 103-{3-[4-((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrol-2-yl-methylene]-2-oxo-2,3-dihydro-4H-indol-5-ylmethyl}-thiazolidine-2,4-dimehydrochloride Step A:3-[4-(1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrol-2-ylmethylene]-5-hydroxymethyl-1,3-dihydro-indol-2-one

A solution of 5-hydroxymethyl-1,3-dihydroindol-2-one (2.75 mmoles), thecompound obtained in Preparation 4 (3.30 mmoles) and piperidine (2.75mmoles) in ethanol is heated at reflux. After 2 hours, the reactionmixture is evaporated and the residue is triturated in AcOEt. Theprecipitate formed is filtered off to yield the title product in theform of a mixture of Z/E isomers (96/4).

Mass spectrometry (ES+, m/z): 336.1706 (M+H)⁺ and 336.1733 (M+H)⁺

Step 13:3-{3-[4-(1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrol-2-yl-methylene}-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the compound obtained in Step B (2.02mmoles) and 5-(4-chloro-benzylidene)-thiazolidine-2,4-dione (3.04mmoles). The product obtained after filtration of the reaction mixtureis purified on silica gel (SiO₂; gradient AcOEt/MeOH) and is thenconverted into the hydrochloride as described in Step E of Example 1 toyield the title product. Mixture of Z/E isomers (97/3)

Mass spectrometry (ES+, m/z): 435.1486 (M+H)⁺ and 435.1493 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 58.66 4.92 11.90 6.81 7.53 Experimental %57.82 4.84 11.58 6.60 7.59

EXAMPLE 113-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-[1,3,4]thiadiazol-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained by following the protocol described inStep E of Example 1, replacing the thiazolidine-2,4-dione by3H-[1,3,4]thiadiazol-2-one. The product obtained after filtration of thereaction mixture is purified on silica gel (SiO₂; gradient AcOEt/MeOH)and is then converted into the hydrochloride as described in Step E ofExample 1 to yield the title product. Mixture of Z/E isomers (97/3)

Mass spectrometry (ES+, m/z): 424.1437 (M+H)⁺ and 424.1459 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 54.84 4.82 15.23 6.97 7.71 Experimental %54.60 4.65 15.07 6.89 7.72

EXAMPLE 125,5-Dimethyl-3-[3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride Step A: 5,5-Dimethyl-thiazolidine-2,4-dione

41.4 mmoles of methyl 2-bromo-2-methyl-propionate and 4.56 mmoles ofthiourea are dissolved in n-butanol (90 mL) and stirred at 110° C. for 5hours. The solvent is evaporated to dryness and the residue is taken upin ethanol (120 ml) and HCl (2N, 120 mL) and then heated at reflux for16 hours. The ethanol is evaporated off and the mixture is diluted withwater (120 ml) and then extracted with AcOEt. The organic phase iswashed with saturated NaCl solution, dried over magnesium sulphate,filtered and evaporated to dryness. The crystals obtained are washedwith pentane, filtered off and dried in vacuo to yield the titleproduct.

Melting point: 76.6° C.

Step B:5,5-Dimethyl-3-[3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride

The title product is obtained by following the protocol described inStep E of Example 1, replacing the thiazolidine-2,4-dione by thecompound obtained in Step A. The product obtained after filtration ofthe reaction mixture is purified on silica gel (SiO₂; gradientAcOEt/MeOH) and is then converted into the hydrochloride as described inStep E of Example 1 to yield the title product. Mixture of Z/E isomers(95/5)

Mass spectrometry (ES+, m/z): 467.1754 (M+H)⁺ and 467.1750 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 57.31 5.41 11.14 6.37 7.05 Experimental %56.99 5.27 11.58 6.30 7.48

EXAMPLE 135-Isopropylidene-3-[3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-yl-methylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride

The title product is obtained by following the protocol described inStep E of Example 1, replacing the thiazolidine-2,4-dione by5-isopropylidene-thiazolidine-2,4-dione. The product obtained afterfiltration of the reaction mixture is purified on silica gel (SiO₂;gradient AcOEt/MeOH) and is then converted into the hydrochloride asdescribed in Step E of Example 1 to yield the title product. Mixture ofZ/E isomers (99/1)

Mass spectrometry (ES+, m/z): 479.1739 (M+H)⁺ and 479.1744 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 58.30 5.28 10.88 6.23 6.88 Experimental %58.09 5.19 10.81 6.35 6.58

EXAMPLE 143-[3-(1-Methyl-4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride Step A:5-Hydroxymethyl-3-(1-methyl-4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one

The title product is obtained following the protocol described in Step Dof Example 1 by condensation of 5-hydroxymethyl-1,3-dihydro-indol-2-one(1.31 mmoles) and the compound obtained in Preparation 6 (1.44 mmoles)in the presence of piperidine in ethanol at 105° C. under microwaveactivation. After evaporation to dryness, the residue is purified onsilica gel (SiO₂; gradient AcOEt/MeOH) to yield the title product.Mixture of Z/E isomers (65/35)

Mass spectrometry (ES+, m/z): 354.1791 (M+H)⁺ and 354.1802 (M+H)⁺

Step B:3-[3-(1-Methyl-4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the compound obtained in Step A (0.88mmole) and thiazolidine-2,4-dione (1.32 mmoles). The product obtainedafter filtration of the reaction mixture is purified on silica gel(SiO₂; gradient AcOEt/MeOH) and is then converted into the hydrochlorideas described in Step E of Example 1 to yield the title product. Mixtureof Z/E isomers (30/70)

Mass spectrometry, (ES+, m/z): 453.1607 (M+H)⁺ and 453.1585 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 56.49 5.15 11.46 6.56 7.25 Experimental %56.29 4.96 11.01 6.68 7.23

EXAMPLE 153-{3-[1-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-yl)-propylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl}-thiazolidine-2,4-dionehydrochloride Step A:5-Hydroxymethyl-3-[1-(4-morpholin-4-ylmethyl-1H-pyrrol-2-yl)-propylidene]-1,3-dihydro-indol-2-one

A solution of 5-hydroxymethyl-1,3-dihydro-indol-2-one (0.22 mmole), thecompound obtained in Preparation 5 (0.44 mmole) and ammonium acetate(0.44 mmole) in n-butanol (4 ml) is heated at 150° C. under microwaveactivation for 1 hour. The product obtained after evaporation of thereaction mixture to dryness is purified on silica gel (SiO₂; gradientAcOEt/MeOH) to yield the title product. Mixture of Z/E isomers (92/8)

Mass spectrometry (ES+, m/z): 368.1941 (M+H)⁺ and 368.1970 (M+H)⁺

Step B3-{3-[1-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-yl)-propylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl}-thiazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the compound obtained in Step A (0.96mmole) and thiazolidine-2,4-dione (1.44 mmoles). The product obtainedafter filtration of the reaction mixture is purified on silica gel(SiO₂; gradient AcOEt/MeOH) and then converted into the hydrochloride asdescribed in Step E of Example 1 to yield the title product. Mixture ofZ/E isomers (98.5/1.5)

Mass spectrometry, (ES+, m/z): 467.1762 (M+H)⁺ and 467.1782 (M+H)⁺

EXAMPLE 165-(4-Hydroxy-2-oxo-thiazolidin-3-ylmethyl)-3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one

To a solution of the compound obtained in Example 1 (1.37 mmoles) in amixture of MeOH/dioxane (42 ml/55 ml) there is added NaBH₄ (2.75 mmoles)at 0° C. The reaction mixture is stirred at ambient temperature for 5hours. The reaction mixture is evaporated to dryness and taken up inwater (20 ml) and is then extracted with AcOEt (4×40 ml). The organicphases are combined. The organic phase is dried over sodium sulphate,filtered and evaporated to dryness. The residue is purified on silicagel (SiO₂; gradient DCM/MeOH) to yield the title product. Mixture of Z/Eisomers (94.5/5.5)

Mass spectrometry, (ES+, m/z): 441.1608 (M+H)⁺ and 441.1621 (M+H)⁺

Elemental Microanalysis:

C H N S Theoretical % 59.98 5.49 12.72 7.28 Experimental % 59.86 5.5812.56 6.93

EXAMPLE 173-[3-(1-Methyl-5-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride Step A:5-Hydroxymethyl-3-(1-methyl-5-morpholin-4-ylmethyl-1H-pyrrol-2-yl-methylene)-1,3-dihydro-indol-2-one

The title product is obtained following the protocol described in Step Dof Example 1 by condensation of 5-hydroxymethyl-1,3-dihydro-indol-2-one(1.84 mmoles) and the compound obtained in Preparation 6 (2.02 mmoles)in the presence of piperidine in ethanol at reflux for 4 hours. Theproduct obtained after evaporation of the reaction mixture to dryness ispurified on silica gel (SiO₂; gradient AcOEt/MeOH) to yield the titleproduct. Mixture of Z/E isomers (22/78)

Mass spectrometry (ES+, m/z): 354.1860 (M+H)⁺ and 376.1577 (M+H)⁺

Step B:3-[3-(1-Methyl-5-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the compound obtained in Step A (1.63mmoles) and thiazolidine-2,4-dione (2.69 mmoles). The product obtainedafter treatment is purified on silica gel (SiO₂; gradient DCM/MeOH) andis then converted into the hydrochloride as described in Step E ofExample 1 to yield the title product. Mixture of Z/E isomers (30/70)

Mass spectrometry, (ES+, m/z): 453.1600 (M+H)⁺ and 453.1559 (M+H)⁺

EXAMPLE 183-[3-(5-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride Step A:5-Hydroxymethyl-3-(5-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one

The title product is obtained following the protocol described in Step Dof Example 1 by condensation of 5-hydroxymethyl-1,3-dihydro-indol-2-one(1.53 mmoles) and the compound obtained in Preparation 7 (1.53 mmoles)in the presence of piperidine in ethanol at reflux for 3 hours. Theprecipitate formed is filtered off and washed with ethanol. The productobtained is dried in vacuo to yield the title product. Mixture of Z/Eisomers (99.8/0.2)

Step B:3-[3-(5-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-thiazolidine-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 1 by condensation of the compound obtained in Step A (1.21mmoles) and thiazolidine-2,4-dione (1.82 mmoles). The product obtainedafter treatment is purified on silica gel (SiO₂; gradient DCM/MeOH) andis then converted into the hydrochloride as described in Step E ofExample 1 to yield the title product. Mixture of Z/E isomers (99.5/0.5)

Elemental Microanalysis:

C H N S Cl− Theoretical % 55.63 4.88 11.80 6.75 7.46 Experimental %55.05 4.81 11.93 6.65 7.65

EXAMPLE 193-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride Step A: 3-(4-Nitro-benzyl)-oxazolidin-2-one

To a suspension of NaH (60% as a dispersion in oil, 0.34 mol) inanhydrous THF (60 ml) at 0° C. there is added, dropwise, a solution ofoxazolidin-2-one (0.31 mol) under an inert atmosphere. The reactionmixture is brought to ambient temperature and stirred for one hour. Asolution of 1-bromomethyl-4-nitro-benzene (0.35 mol) in a mixture ofTHF/DMF (10/1) (250 ml) is added dropwise at 0° C. The reaction mixtureis then stirred overnight at ambient temperature. The solution is thencooled to 0° C. There are then added, in succession, 20 ml of MeOH and20 ml of water. The suspension obtained is then concentrated and thenpoured into 500 ml of water. The solution is then extracted with DCM andthe organic phases are combined. The organic phase obtained is washedwith water and with saturated aqueous NaCl solution, is dried oversodium sulphate and is then filtered. The filtrate obtained isconcentrated and the solid formed is filtered off, washed with ethylether and then dried in vacuo to yield the title product, which is useddirectly in the next Step.

Step B: 3-(4-Amino-benzyl)-oxazolidin-2-one

A solution of the compound obtained in Step A (0.244 mol) and SnCl₂.2H₂O(1.0 mol) in ethanol (300 ml) is stirred at reflux for 20 minutes. Thesolution is brought to 0° C. and made alkaline at pH=10-12 with aqueoussodium hydroxide solution; 500 ml of DCM are added and the emulsionobtained is filtered over Celite. The filtrate is then extracted withDCM (2×300 ml); the organic phases are combined. The organic phaseobtained is washed with water and with saturated aqueous NaCl solution,dried over sodium sulphate and then filtered. The filtrate obtained isevaporated to dryness to yield the title product, which is used directlyin the next Step.

Step C:3-Methylsulphanyl-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one

To a solution of the compound obtained in Step B (0.113 mol) in amixture of CH₃CN (200 ml) and THF (200 ml) at −60° C. there is added,dropwise, ethyl (methylsulphanyl)-acetate (0.136 mol) under a nitrogenatmosphere. tBuOCl (0.136 mol) is added dropwise to the reaction mixtureover 20 minutes, keeping the temperature between −60° C. and −55° C.After stiffing for one hour at −50° C., triethylamine (0.152 mol) isadded dropwise. The reaction mixture is brought to 0° C. and thenaqueous 3M HCl solution (580 ml) is added dropwise. After stiffing for12 hours at ambient temperature, the organic phases are evaporated invacuo and then the aqueous phase is extracted with DCM and the organicphases are combined. The organic phase obtained is washed with water andthen with saturated aqueous NaCl solution. The organic phase is driedover sodium sulphate, filtered and evaporated to dryness. The productobtained is recrystallised from a mixture of ethyl ether/ethanol. Thecrystals obtained are filtered off, washed with ether and dried in vacuoat 40° C. to yield the title product, which is used directly in the nextStep.

Step D: 5-(2-Oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one

To a solution of the compound obtained in Step C in glacial acetic acid(320 ml) there is added powdered zinc (1 mol). The reaction mixture isstirred overnight at ambient temperature and is then filtered. Thefiltrate is concentrated, and then 100 ml of water are added. The solidformed is filtered off and then recrystallised from ethanol to yield thetitle product.

Mass spectrometry (ES+, m/z): 233.0905 (M+H)⁺

Step E:3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

A solution of the compound obtained in Step D (18.8 mmoles), thecompound obtained in Preparation 1 (20.7 mmoles) and piperidine (13.2mmoles) in EtOH (100 mL) is stirred at reflux for 3 hours and then atambient temperature for 12 hours. The yellow solid obtained is filteredwith water and ethanol. The product obtained is dissolved in the hotstate in 300 ml of a mixture of DCM/MeOH (1/1). The solution is broughtto ambient temperature and 40 ml of HCl solution (1.25M) in ethanol areadded. The yellow solid formed is filtered off under nitrogen, washedwith ethyl ether and dried at 40° C. in vacuo over 12 hours to yield thetitle product. Mixture of Z/E isomers (99/1).

Mass spectrometry (ES+, m/z): 409.1863 (M+H)⁺ and 409.1886 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 59.39 5.66 12.59 7.97 Experimental % 60.02 5.5612.79 8.10

EXAMPLE 203-(5-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolid-in-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.5 mmoles) andthe compound obtained in Preparation 7 (1.65 mmoles) in the presence ofpiperidine in ethanol at reflux. After evaporation of the reactionmixture to dryness, the residue obtained is purified by flashchromatography on silica gel (SiO₂; gradient c-Hexane/AcOEt). Theproduct obtained is converted into the hydrochloride as described inStep E of Example 19 to yield the title product. Mixture of Z/E isomers(98.3/1.7)

Mass spectrometry (ES+, m/z): 409.1881 (M+H)⁺ and 409.1892 (M+H)⁺

Melting point: 195° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 59.39 5.66 12.59 7.97 Experimental % 60.03 5.3912.65 8.14

EXAMPLE 213-(3-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.4 mmoles) andthe compound obtained in Preparation 8 (1.7 mmoles) in the presence ofpiperidine in ethanol at reflux. The product obtained after evaporationto dryness is purified by flash chromatography on silica gel (SiO₂;gradient DCM to DCM/MeOH 9/1) to yield the title product. Mixture of Z/Eisomers (90/10)

Mass spectrometry (ES+, m/z): 409.1856 (M+H)⁺ and 409.1867 (M+H)⁺

Melting point: 192° C.

Elemental Microanalysis:

C H N Theoretical % 64.69 5.92 13.72 Experimental % 64.37 5.73 13.73

EXAMPLE 223-[1-(4-Morpholin-4-ylmethyl-4H-pyrrol-2-yl)-ethylidene]-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

A mixture of the compound obtained in Preparation 2 (3.22 mmoles),5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (2.15 mmoles)and NH₄OAc (9.73 mmoles) in ethanol is heated under microwaves at 110°C. for 45 minutes. The precipitate formed is filtered off and is thensuspended in water and heated again for 10 minutes at 110° C. undermicrowaves. The solid obtained is filtered off, suspended in ethanol andheated again for 10 minutes at 110° C. under microwaves. The productobtained is converted into the hydrochloride as described in Step E ofExample 19 to yield the title product. Mixture of Z/E isomers (99.5/0.5)

Mass spectrometry, (ES+, m/z): 423.2012 (M+H)⁺ and 423.2056 (M+H)⁺

Melting point: 212° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 60.19 5.93 12.21 7.72 Experimental % 59.88 5.7311.82 8.00

EXAMPLE 233-(5-Diethylaminomethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.72 mmoles)and the compound obtained in Preparation 9 (1.9 mmoles) in the presenceof piperidine in ethanol at reflux. The product obtained afterfiltration of the reaction mixture is purified by flash chromatographyon silica gel (SiO₂; gradient 100% DCM to DCM/MeOH 9/1). The productobtained is converted into the hydrochloride as described in Step E ofExample 19 to yield the title product. Mixture of Z/E isomers (99.5/0.5)

Mass spectrometry, (ES+, m/z): 393.1933 (M+H)⁺ and 393.1933 (M+H)⁺

Melting point: 238° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 61.32 6.31 13.00 8.23 Experimental % 61.44 6.3113.37 8.33

EXAMPLE 24(1R,5S)-3-[3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-3-aza-bicyclo[3.1.0]hexane-2,4-dionehydrochloride Step A:3-Methylsulphanyl-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To a solution of 4-amino-benzonitrile (84.64 mmoles) in DCM (200 ml)under a nitrogen atmosphere, at −78° C., there is added, dropwise,tBuOCl (84.64 mmoles) dissolved in 20 ml of DCM and then, after 10minutes, ethyl (methylsulphanyl)acetate (84.64 mmoles) dissolved in 20ml of DCM is added dropwise to the reaction mixture. After stiffing forone hour at −78° C., triethylamine (0.152 mol) is added dropwise. Thereaction mixture is stirred at ambient temperature for one hour. Wateris added and the phases are then separated. The organic phase is washedwith water and then with saturated aqueous NaCl solution. The organicphase is dried over sodium sulphate, filtered and evaporated to dryness.The residue is taken up in ethyl ether and aq. 2M HCl solution is added.After stiffing overnight, the yellow precipitate is filtered off anddried in vacuo to yield the title product, which is used directly in thenext reaction.

Step B: 2-Oxo-2,3-dihydro-1H-indole-5-carbonitrile

To a suspension of Raney nickel in THF (100 ml) there is added thecompound obtained in Step A (20 mmoles) dissolved in THF (400 ml). Thereaction mixture is stirred at ambient temperature until the startingmaterial has completely disappeared. The reaction mixture is thenfiltered over a bed of Celite and then evaporated to dryness to yieldthe title product, which is used directly in the next reaction.

Step C: 5-Aminomethyl-1,3-dihydro-indol-2-one

A solution of the compound obtained in Step B (35 mmoles) in MeOH (500ml) is added to 6 ml of concentrated HCl. The reaction mixture isstirred for 3 days under 10 bars of hydrogen. After filtration overCelite, the filtrate is evaporated to dryness to yield the title productin the form of a white powder, which is used directly in the nextreaction.

Step D:(1R,5S)-3-(2-Oxo-2,3-dihydro-4H-indol-5-ylmethyl)-3-aza-bicyclo[3.1.0]-hexane-2,4-dione

A solution of the compound obtained in Step C (15 mmoles) and3-oxa-bicyclo[3.1.0]-hexane-2,4-dione (22.5 mmoles) in acetic acid (60ml) is heated at reflux for 48 hours. The mixture is brought to ambienttemperature and the solid formed is filtered off to yield the titleproduct, which is used directly in the next reaction.

Mass spectrometry (ES+, m/z): 257.0913 (M+H)⁺

Step E:(1R,5S)-3-[3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl]-3-aza-bicyclo[3.1.0]hexane-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step D (1.54mmoles) and the compound obtained in Preparation 1 (1.7 mmoles) in thepresence of piperidine in ethanol at reflux. The product obtained afterfiltration of the reaction mixture is converted into the hydrochlorideas described in Step E of Example 19 to yield the title product. Mixtureof Z/E isomers (98.5/1.5)

Mass spectrometry (ES+, m/z): 433.1857 (M+H)⁺ and 433.1861 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 61.47 5.37 11.95 7.56 Experimental % 61.01 5.5012.03 7.21

EXAMPLE 253-(3,5-Dimethyl-4-morpholin-4′-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride Step A:3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one

A solution of 5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one(4.3 mmoles), 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (5.17 mmoles) andpiperidine (3 mmoles) in ethanol (30 ml) is heated at reflux for 24hours. The solid formed is filtered off, washed with ethanol, with waterand then with ethanol and dried in vacuo to yield the title product.

Mass spectrometry (ES+, m/z): 338.1485 (M+H)⁺

Step B:3-(3,5-Dimethyl-4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmeth1)-1,3-dihydro-indol-2-one hydrochloride

To a solution of the compound obtained in Step A (1.3 mmoles) in aceticacid (20 ml) there are added at 0° C. morpholine (1.43 mmoles) andformaldehyde (37% aq., 1.3 mmoles). The reaction mixture is stirredovernight at ambient temperature. The mixture is evaporated to drynessand the residue is purified on silica gel (SiO₂; gradient 100% DCM toDCM/MeOH 9/1). The product obtained is converted into the hydrochlorideas described in Step E of Example 19 to yield the title product. Mixtureof Z/E isomers (99.5/0.5)

Mass spectrometry (ES+, m/z): 435.2036 (M+H)⁺ and 435.2035 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 60.95 6.18 11.85 7.50 Experimental % 60.13 5.8811.81 7.70

EXAMPLE 263-[3,5-Dimethyl-4-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrol-2-yl-methylene]-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onedihydrochloride

To a solution of the compound obtained in Step A of Example 25 (1.18mmoles) in acetic acid (20 ml) there are added at 0° C.1-methyl-piperazine (1.18 mmoles) and formaldehyde (37% aq., 1.18mmoles). The reaction mixture is stirred overnight at ambienttemperature. After acid-base extraction, the product obtained isconverted into the hydrochloride as described in Step E of Example 19 toyield the title product. Z isomer.

Mass spectrometry (ES+, m/z): 448.2377 (M+H)⁺

Melting point: 230° C. (decomposition)

EXAMPLE 273-(3,5-Dimethyl-4-piperidin-1-ylmethyl-4H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmeth1)-1,3-dihydro-indol-2-one hydrochloride

To a solution of the compound obtained in Step A of Example 25 (1.48mmoles) in acetic acid (20 ml) there are added, at 0° C., piperidine(1.48 mmoles) and formaldehyde (37% aq., 1.48 mmoles). The reactionmixture is stirred overnight at ambient temperature. After acid-baseextraction, the product obtained is purified on silica gel (SiO₂;gradient 100% DCM to DCM/MeOH 9/1) and then converted into thehydrochloride as described in Step E of Example 19 to yield the titleproduct. Mixture of Z/E isomers (98.5/1.5)

Mass spectrometry (ES+, m/z): 435.2367 (M+H)⁺ and 435.2382 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 63.75 6.63 11.90 7.53 Experimental % 63.79 6.3611.87 7.82

EXAMPLE 283-(4-Morpholin-4-ylmethyl-4H-pyrrol-2-ylmethylene)-5-(2-oxo-thiazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride Step A:5-(2-Oxo-thiazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one

The title product is obtained as in Steps A to D of Example 19,replacing the oxazolidin-2-one by thiazolidin-2-one in Step A.

Step B:3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-thiazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step A (1.54mmoles) and the compound obtained in Preparation 1 (1.7 mmoles) in thepresence of piperidine in ethanol at reflux. The product obtained afterfiltration of the reaction mixture is purified on silica gel (SiO₂;gradient 100% DCM to DCM/MeOH 9/1) and is then converted into thehydrochloride as described in Step E of Example 19 to yield the titleproduct. Mixture of Z/E isomers (99/1)

Mass spectrometry (ES+, m/z): 425.1633 (M+H)⁺ and 425.1679 (M+H)⁺

Melting point: 244° C.

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 57.32 5.47 12.15 6.96 7.69 Experimental %56.55 5.30 11.80 6.74 8.13

EXAMPLE 293-[4-(4-Methyl-piperazin-1-ylmethyl)-1,1-pyrrol-2-ylmethylene]-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onedihydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.66 mmoles)and the compound obtained in Preparation 10 (2.07 mmoles) in thepresence of piperidine in ethanol at reflux. The product obtained afterevaporation of the reaction mixture to dryness is purified on silica gel(SiO₂; gradient 100% DCM to DCM/MeOH 9/1) and is then converted into thehydrochloride as described in Step E of Example 19 to yield the titleproduct. Mixture of Z/E isomers (98/2)

Mass spectrometry (ES+, m/z): 422.2183 (M+H)⁺ and 422.2198 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 55.87 5.91 14.17 14.34 Experimental % 56.15 5.6514.30 14.22

EXAMPLE 305-[5-(4-Chloro-phenyl)-2-oxo-6,1-[1,3,4]thiadiazin-3-ylmethyl]-3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-onehydrochloride Step A:5-(4-Chloro-phenyl)-3,6-dihydro-[1,3,4]thiadiazin-2-one

A mixture of 2-bromo-1-(4-chloro-phenyl)-ethanone (90.71 mmoles) andhydrazine-carbothioic acid O-ethyl ester (90.71 mmoles) in acetonitrile(84 ml) is stirred at ambient temperature for 3 hours. The solid formedis filtered off, washed with acetonitrile and ethyl ether and then driedin vacuo to yield the title product, which is used directly in the nextStep.

Step B:5-(4-Chloro-phenyl)-3-(4-nitro-benzyl)-3,6-dihydro-[1,3,4]thiadiazin-2-one

To a solution of the compound obtained in Step A (57.83 mmoles) inacetonitrile (260 ml) there are added 1-bromomethyl-4-nitro-benzene(63.61 mmoles) and potassium carbonate (231.32 mmoles). The reactionmixture is stirred at 80° C. for 1 hour under nitrogen. The reactionmixture is brought to ambient temperature and 100 ml of water are added.Extraction with ethyl ether (3×350 ml) is carried out and the organicphases are combined. The organic phase obtained is dried over sodiumsulphate, filtered and evaporated to dryness. The solid is triturated inethyl ether, filtered off and dried in vacuo to yield the title product,which is used directly in the next Step.

Step C:3-(4-Amino-benzyl)-5-(4-chloro-phenyl)-3,6-dihydro-[1,3,4]thiadiazin-2-one

The compound obtained in Step B is reduced under the conditionsdescribed hereinbefore in Step B of Example 19 to yield the titleproduct, which is used directly in the next Step.

Step D:5-[5-(4-Chloro-phenyl)-2-oxo-6H-[1,3,4]thiadiazin-3-ylmethyl]-3-methylsulphanyl-1,3-dihydro-indol-2-one

To a solution of the compound obtained in Step C (38.27 mmoles), in amixture of CH₃CN (115 ml) and THF (115 ml) at −60° C., ethyl(methylsulphanyl)acetate (45.92 mmoles) is added dropwise under anitrogen atmosphere. ^(t)BuOCl (45.92 mmoles) is added dropwise to thereaction mixture over 20 minutes, keeping the temperature between −60°C. and −55° C. After stirring for 1 hour at −60° C., triethylamine(51.66 mmoles) is added dropwise. The reaction mixture is brought toambient temperature. 240 ml of DCM and then aqueous 3M HCl solution (340ml) are added. After stiffing for 12 hours at ambient temperature, thereaction mixture is made alkaline (pH 10-11) using 20% aqueous sodiumhydroxide solution. After extraction with DCM, the organic phase iswashed with saturated aqueous NaCl solution. The organic phase is driedover sodium sulphate, filtered and evaporated to dryness. The productobtained is triturated in ethyl ether, filtered and dried in vacuo toyield the title product which is used directly in the next Step.

Step E:5-[5-(4′-Chloro-phenyl)-2-oxo-6H-[1,3,4]thiadiazin-3-ylmethyl]-1,3-dihydro-indol-2-one

Powdered zinc (18.09 mmoles) is added to a solution of the compoundobtained in Step D (27.68 mmoles) in glacial acetic acid (350 ml). Thereaction mixture is stirred overnight at ambient temperature and thenfiltered. The filtrate is concentrated and then brought to pH 8-9 withsaturated aqueous sodium bicarbonate solution and sonicated for 5minutes. The solid formed is filtered off and then recrystallised fromethanol to yield the title product.

Mass spectrometry (ES+, m/z): 372.0561 (M+H)⁺

Elemental Microanalysis:

C H N S Theoretical % 58.14 3.79 11.30 8.62 Experimental % 57.38 3.5411.12 8.18

Step F:5-[5-(4-Chloro-phenyl)-2-oxo-6H-[1,3,4]thiadiazin-3-ylmethyl]-3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step E (1.34mmoles) and the compound obtained in Preparation 1 (1.5 mmoles) in thepresence of piperidine in ethanol at reflux. The product obtained afterfiltration of the reaction mixture is converted into the hydrochlorideas described in Step E of Example 19 to yield the title product. Mixtureof Z/E isomers (98/2)

Mass spectrometry (ES+, m/z): 548.1517 (M+H)⁺ and 548.1540 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 57.54 4.66 11.98 5.49 6.07 Experimental %56.56 4.76 11.61 5.25 5.73

EXAMPLE 315-(2-Oxo-oxazolidin-3-ylmethyl)-3-(4-pyrrolidin-1-ylmethyl-1-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.08 mmoles)and the compound obtained in Preparation 11 (1.08 mmoles) in thepresence of piperidine in ethanol at reflux. After filtration, the solidobtained is purified on silica gel (SiO₂; AcOEt/MeOH 7/3) and thenconverted into the hydrochloride as described in Step E of Example 19 toyield the title product. Mixture of Z/E isomers (97/3)

Mass spectrometry (ES+, m/z): 393.1899 (M+H)⁺ and 393.1896 (M+H)⁺

Melting point: 204° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 61.61 5.87 13.06 8.27 Experimental % 61.33 5.8313.01 8.61

EXAMPLE 323-[4-((3aR,6aS)-Hexahydro-cyclopenta[c]pyrrol-2-(1H)-ylmethyl)-1H-pyrrol-2-ylmethylene]-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.08 mmoles)and the compound obtained in Preparation 12 (1.13 mmoles) in thepresence of piperidine in ethanol at reflux. After filtration, the solidobtained is converted into the hydrochloride as described in Step E ofExample 19 to yield the title product. Mixture of Z/E isomers (96/4)

Mass spectrometry (ES+, m/z): 433.2212 (M+H)⁺ and 433.2217 (M+H)⁺

Melting point: 237° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 64.03 6.23 11.95 7.56 Experimental % 63.57 6.1111.92 7.42

EXAMPLE 335-(2-Oxo-oxazolidin-3-ylmethyl)-3-(4-piperidin-1-ylmethyl-4H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol in Step E ofExample 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.08 mmoles)and the compound obtained in Preparation 13 (1.13 mmoles) in thepresence of piperidine in ethanol at reflux. After filtration, the solidobtained is converted into the hydrochloride as described in Step E ofExample 19 to yield the title product. Mixture of Z/E isomers (97/3)

Mass spectrometry (ES+, m/z): 407.2047 (M+H)⁺ and 407.2053 (M+H)⁺

Melting point: 256° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 62.37 6.14 12.65 8.00 Experimental % 62.36 6.0412.78 7.99

EXAMPLE 343-(4-Diethylaminomethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.08 mmoles)and the compound obtained in Preparation 14 (1.08 mmoles) in thepresence of piperidine in ethanol at reflux. After filtration, the solidobtained is purified on silica gel (SiO₂; gradient AcOEt to AcOEt/MeOH7/3) and then converted into the hydrochloride as described in Step E ofExample 19 to yield the title product. Mixture of Z/E isomers (93/7)

Mass spectrometry (ES+, m/z): 395.2066 (M+H)⁺ and 395.2082 (M+H)⁺

Melting point: 192° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 61.61 5.87 13.06 8.27 Experimental % 61.33 5.8313.01 8.61

EXAMPLE 355-[5-(4-Chloro-phenyl)-2-oxo-6H-[1,3,4]thiadiazin-3-ylmethyl]-3-[1-(4-morpholin-4-ylmethyl-4H-pyrrol-2-yl)-ethylidene]-1,3-dihydro-indol-2-onehydrochloride

A mixture of the compound obtained in Step E of Example 30 (1 mmole),the compound obtained in Preparation 2 (1.5 mmoles) and NH₄OAc (4.5mmoles) in ethanol is heated under microwaves at 110° C. for 20 minutes.After filtration, the solid obtained is purified on silica gel (SiO₂;gradient AcOEt to AcOEt/MeOH 9/1) and then converted into thehydro-chloride as described in Step E of Example 19 to yield the titleproduct. Mixture of Z/E isomers (98/2)

Mass spectrometry (ES+, m/z): 562.1647 (M+H)⁺ and 562.1666 (M+H)⁺

Elemental Microanalysis:

C H N S Theoretical % 57.76 5.47 10.86 4.97 Experimental % 57.65 5.5610.86 4.88

EXAMPLE 363-[4-((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-3,5-dimethyl-4H-pyrrol-2-ylmethylene]-5-(2-oxo-oxazolidin-3-ylmethyl)-4,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (0.63 mmole) andthe compound obtained in Preparation 3 (0.69 mmole) in the presence ofpiperidine in ethanol at 110° C. under microwave activation. Afterfiltration, the solid obtained is purified on silica gel (SiO₂; gradientAcOEt/MeOH) and then converted into the hydrochloride as described inStep E of Example 19 to yield the title product. Mixture of Z/E isomers(93/7)

Mass spectrometry (ES+, m/z): 431.2070 (M+H)⁺ and 431.2074 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 64.03 6.23 11.95 7.56 Experimental % 64.21 6.2712.18 7.82

EXAMPLE 37(1R,5S)-3-[2-Oxo-3-(4-piperidin-1-ylmethyl-1H-pyrrol-2-ylmethylene)-2,3-dihydro-1H-indol-5-ylmethyl]-3-aza-bicyclo[3.1.0]hexane-2,4-dionehydrochloride

The title product is obtained following the protocol described in Step 5of Example 19 by condensation of(1R,55)-3-(2-oxo-2,3-dihydro-1H-indol-5-ylmethyl)-3-aza-bicyclo[3.1.0]-hexane-2,4-dione(0.62 mmole) and the compound obtained in Preparation 13 (0.65 mmole) inthe presence of piperidine in ethanol at reflux. The product obtainedafter filtration of the reaction mixture is converted into thehydrochloride as described in Step E of Example 19 to yield the titleproduct. Mixture of Z/E isomers (98.5/1.5)

Mass spectrometry (ES+, m/z): 431.2056 (M+H)⁺ and 431.2077 (M+H)⁺

Melting point: 198° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 64.30 5.83 12.00 7.59 Experimental % 63.52 5.8012.16 8.18

EXAMPLE 383-[4-[((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl]-1H-pyrrol-2-yl-methylene]-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of3-(5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.5 mmoles)and the compound obtained in Preparation 4 (1.9 mmoles) in the presenceof piperidine at the reflux of ethanol overnight. The product obtainedafter filtration of the reaction mixture is converted into thehydrochloride as described in Step E of Example 19 to yield the titleproduct. Mixture of Z/E isomers (94.5/5.5)

Mass spectrometry (ES+, m/z): 405.1923 (M+H)⁺ and 405.1926 (M+H)⁺

Melting point: 179° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 62.65 5.71 12.71 8.04 Experimental % 62.45 5.7312.88 8.75

EXAMPLE 393-[4-((3aR,6aS)-Hexahydro-cyclopenta[c]pyrrol-2(1H)-ylmethyl)-3,5-dimethyl-1R-pyrrol-2-ylmethylene]-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.72 mmoles)and the compound obtained in Preparation 15 (2.06 mmoles) in thepresence of piperidine in ethanol at reflux. After filtration, the solidobtained is converted into the hydrochloride as described in Step E ofExample 19 to yield the title product. Mixture of Z/E isomers (96.5/3.5)

Mass spectrometry (ES+, m/z): 461.2549 (M+H)⁺ and 461.2566 (M+H)⁺

Melting point: 204° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 65.25 6.69 11.27 7.13 Experimental % 64.82 6.3211.21 7.24

EXAMPLE 403-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-piperidin-1-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride Step A:5-(2-Oxo-piperidin-1-ylmethyl)-1,3-dihydro-indol-2-one

The title product is obtained in accordance with Steps A to D of Example19, using piperidin-2-one in Step A.

Mass spectrometry, (ES+, m/z): 245.1275 (M+H)⁺

Step B:3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-piperidin-1-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step A (1.3mmoles) and the compound obtained in Preparation 1 (1.3 mmoles) in thepresence of piperidine in ethanol at reflux. After filtration, the solidobtained is converted into the hydrochloride as described in Step E ofExample 19 to yield the title product. Mixture of Z/E isomers (98.5/1.5)

Mass spectrometry (ES+, m/z): 421.2222 (M+H)⁺ and 421.2245 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 63.08 6.40 12.26 7.76 Experimental % 63.15 6.2512.12 7.87

EXAMPLE 413-{[(4-Morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-5-[(1,1-dioxido-2-isothiazolidinyl)meth1]-1,3-dihydro-2H-indol-2-one hydrochloride Step A:5-[(1,1-Dioxido-2-isothiazolidinyl)methyl]-1,3-dihydro-2H-indol-2-one

The title product is obtained by following the protocol described inSteps A to D of Example 19, using isothiazolidine 1,1-dioxide in Step A.

Mass spectrometry (ES+, m/z): 267.0796 (M+H)⁺

Step B:3-{[(4-Morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-5-[(1,1-dioxido-2-isothiazolidinyl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step A (1.32mmoles) and the compound obtained in Preparation 1 (1.65 mmoles) in thepresence of piperidine in ethanol at reflux. The product obtained afterevaporation of the reaction mixture to dryness is purified on silica gel(SiO₂; gradient AcOEt/MeOH) and then converted into the hydrochloride asdescribed in Step E of Example 19 to yield the title product. Mixture ofZ/E isomers (99.5/0.5)

Mass spectrometry, (ES+, m/z): 443.1746 (M+H)⁺ and 443.1758 (M+H)⁺

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 55.17 5.68 11.70 6.69 7.40 Experimental %54.42 5.64 11.58 6.55 7.50

EXAMPLE 423-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-pyrrolidin-1-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride Step A:5-(2-Oxo-pyrrolidin-1-ylmethyl)-1,3-dihydro-indol-2-one

The title product is obtained by following the protocol described inSteps A to D of Example 19, using pyrrolidin-2-one in Step A.

Mass spectrometry (ES+, m/z): 231.1120 (M+H)⁺

Step B:3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-pyrrolidin-1-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step A (1.63mmoles) and the compound obtained in Preparation 1 (1.95 mmoles) in thepresence of piperidine in ethanol at reflux. The product obtained afterfiltration is purified on silica gel (SiO₂; gradient DCM/MeOH) and thenconverted into the hydrochloride as described in Step E of Example 19 toyield the title product. Mixture of Z/E isomers (99.5/0.5)

Mass spectrometry (ES+, m/z): 407.2056 (M+H)⁺ and 407.2065 (M+H)⁺

EXAMPLE 433-(1-Methyl-4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-4,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (1.31 mmoles)and the compound obtained in Preparation 6 (1.44 mmoles) in the presenceof piperidine in ethanol at reflux. The product obtained afterevaporation of the reaction mixture to dryness is purified on silica gel(SiO₂; gradient AcOEt/MeOH) and then converted into the hydrochloride asdescribed in Step E of Example 19 to yield the title product. Mixture ofZ/E isomers (33/66)

Mass spectrometry (ES+, m/z): 423.2034 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 60.19 5.93 12.21 7.72 Experimental % 59.54 5.7312.09 8.10

EXAMPLE 443-[4-((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrol-2-yl-methylene]-5-[5-(4-chloro-phenyl)-2-oxo-6H-[1,3,4]oxadiazin-3-ylmethyl]-1,3-dihydro-indol-2-onehydrochloride Step A: 1-(4-Chloro-phenyl)-2-hydroxy-ethanone

A mixture of 2-bromo-1-(4-chloro-phenyl)-ethanone (100 mmoles) andpotassium formate (130 mmoles) in MeOH (100 ml) is stirred at reflux for3 hours. The reaction mixture is poured onto crushed ice. The solidformed is filtered off, washed with cold MeOH and then dried in vacuo toyield the title product, which is used directly in the next Step.

Step B: EthylN′-[1-(4-chloro-phenyl)-2-hydroxy-ethylidene]-hydrazinecarboxylate

A mixture of the compound obtained in Step A (195 mmoles) and ethylhydrazinecarboxylate (224 mmoles) in ethanol is stirred at reflux for 18hours. The reaction mixture is cooled to 0° C. and the precipitateformed is filtered off, washed with ethyl ether and dried in vacuo toyield the title product, which is used directly in the next Step.

Step C: 5-(4-Chloro-phenyl)-3,6-dihydro-[1,3,4]oxadiazin-2-one

Sodium hydride (60% in oil, 16 mmoles) is added, in small portions andat ambient temperature, to a solution of the compound obtained in Step B(100.5 mmoles) in ethanol (800 ml). After reacting for 2 hours, thereaction mixture is cooled to 0° C. and stiffing is continued for 30minutes. The precipitate formed is filtered off, washed with coldethanol and then dried in vacuo to yield the title product, which isused directly in the next Step.

Mass spectrometry (ES+, m/z): 211.0277 (M+H)⁺

Step D:5-(4-Chloro-phenyl)-3-(4-nitro-benzyl)-3,6-dihydro-[1,3,4]oxadiazin-2-one

To a solution of the compound obtained in Step C (47.48 mmoles) inacetonitrile (260 ml) there are added 1-bromomethyl-4-nitro-benzene(52.23 mmoles) and potassium carbonate (189.92 mmoles). The reactionmixture is stirred at reflux for 4 hours under nitrogen. The reactionmixture is brought to ambient temperature and then diluted with 500 mlof DCM and 100 ml of water. Extraction with DCM (2×200 ml) is carriedout and then the organic phases are combined. The organic phase obtainedis washed with saturated NaCl solution and is then dried over sodiumsulphate, filtered and concentrated to about 75 ml. After formation of aprecipitate in suspension, ethyl ether (150 ml) is added, and stirred iscarried out overnight at ambient temperature. The precipitate isfiltered off, washed with ethyl ether and dried in vacuo to yield thetitle product, which is used directly in the next Step.

Step E:3-(4-Amino-benzyl)-5-(4-chloro-phenyl)-3,6-dihydro-[1,3,4]oxadiazin-2-one

A suspension of the compound obtained in Step D (42.02 mmoles) in amixture of EtOH (350 ml) and acetic acid (26 ml) is heated at reflux for5 minutes. Powdered iron (309 mmoles) and FeCl₃.6H₂O (2.1 mmoles) areadded to the resulting solution. The reaction mixture is stirred atreflux overnight. After evaporation, water (250 ml) is added to theresidue and then sonicated for 2 minutes. The mixture is made alkaline(pH 12) using aqueous 2M sodium hydroxide solution, then diluted withAcOEt (500 ml) and then filtered over Celite. The phases are separatedand the aqueous phase is extracted with AcOEt. The organic phases arecombined. The organic phase obtained is washed with water and then withsaturated NaCl solution, dried over sodium sulphate, filtered andevaporated to dryness. The residue is triturated in ethyl ether,filtered and dried in vacuo to yield the title product in the form of awhite powder, which is used directly in the next Step.

Step F:5-[5-(4-Chloro-phenyl)-2-oxo-6H-[1,3,4]oxadiazin-3-ylmethyl]-3-methyl-sulphanyl-1,3-dihydro-indol-2-one

Ethyl (methylsulphanyl)acetate (27.31 mmoles) is added dropwise to asolution of the compound obtained in Step E (23.75 mmoles) in THF (200ml) at −60° C. under a nitrogen atmosphere. ^(t)BuOCl (27.31 mmoles) isadded dropwise to the reaction mixture over 20 minutes, keeping thetemperature between −60° C. and −55° C. After stirring for 3 hours at−60° C., triethylamine (29.68 mmoles) is added dropwise. The reactionmixture is brought to ambient temperature; aqueous 3M HCl solution (340ml) is then added and stirring is carried out for a further 2 hours. Theorganic phase is evaporated and the aqueous suspension is extracted withDCM. The organic phases are combined, then washed with 2M HCl solutionand then with saturated NaCl solution, dried over sodium sulphate,filtered and evaporated to dryness. The residue is triturated in ethylether, filtered and dried in vacuo to yield the title product, which isused directly in the next Step.

Step G:5-[5-(4-Chloro-phenyl)-2-oxo-6H-[1,3,4]oxadiazin-3-ylmethyl]-1,3-dihydro-indol-2-one

Powdered Zn (157.3 mmoles) is added to a solution of the compoundobtained in Step F (15.73 mmoles) in glacial acetic acid (150 ml). Thereaction mixture is stirred for 6 hours and then filtered. The filtrateis evaporated to dryness and then taken up in water (200 ml) and DCM(400 ml). The phases are separated and the aqueous phase is extractedwith DCM; the organic phases are combined. The organic phase obtained iswashed with water and then with saturated NaCl solution, dried oversodium sulphate, filtered and evaporated to dryness. The residueobtained is recrystallised from ethanol to yield the title product.

Mass spectrometry, (ES+, m/z): 356.0796 (M+H)⁺

Step H:3-[4-((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrol-2-ylmethylene]-5-[5-(4-chloro-phenyl)-2-oxo-6H-[1,3,4]oxadiazin-3-ylmethyl]-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step G (1.2mmoles) and the compound obtained in Preparation 4 (1.38 mmoles) in thepresence of piperidine in ethanol at reflux. The product obtained afterevaporation of the reaction mixture to dryness is purified on silica gel(SiO₂; gradient DCM/MeOH) and then converted into the hydrochloride asdescribed in Step E of Example 19 to yield the title product. Mixture ofZ/E isomers (94.5/5.5)

Mass spectrometry (ES+, m/z): 528.1808 (M+H)⁺ and 528.1803 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 61.71 4.82 12.41 6.28 Experimental % 61.91 4.4312.51 7.52

EXAMPLE 455-[5-(4-Chloro-phenyl)-2-oxo-6H-[1,3,4]oxadiazin-3-ylmethyl]-3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-[5-(4-chloro-phenyl)-2-oxo-6H[1,3,4]oxadiazin-3-ylmethyl]-1,3-dihydro-indol-2-one(1.2 mmoles) and the compound obtained in Preparation 1 (1.38 mmoles) inthe presence of piperidine in ethanol at reflux. The product obtainedafter evaporation of the reaction mixture to dryness is purified onsilica gel (SiO₂; gradient DCM/MeOH) and then converted into thehydrochloride as described in Step E of Example 19 to yield the titleproduct. Mixture of Z/E isomers (98/2)

Mass spectrometry (ES+, m/z): 532.1721 (M+H)⁺ and 532.1749 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 59.16 4.79 12.32 6.24 Experimental % 58.71 4.7312.33 6.37

EXAMPLE 463-(5-Morpholin-4-ylmethyl-1H-pyrrol-3-ylmethylene)-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (0.86 mmole) andthe compound obtained in Preparation 16 (0.91 mmole) in the presence ofpiperidine in ethanol at reflux. The product obtained after evaporationof the reaction mixture to dryness is purified on silica gel (SiO₂;gradient DCM/MeOH) and then converted into the hydrochloride asdescribed in Step E of Example 19 to yield the title product. Mixture ofZ/E isomers (78/22)

Mass spectrometry (ES+, m/z): 409.1883 (M+H)⁺ and 409.1865 (M+H)⁺

EXAMPLE 473-[5-((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrol-3-yl-methylene]-5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (0.95 mmole) andthe compound obtained in Preparation 17 (0.95 mmole) in the presence ofpiperidine in ethanol at reflux. The product obtained after evaporationof the reaction mixture to dryness is purified on silica gel (SiO₂;gradient DCM/MeOH) and then converted into the hydrochloride asdescribed in Step E of Example 19 to yield the title product. Mixture ofZ/E isomers (82/18)

Mass spectrometry (ES+, m/z): 405.1931 (M+H)⁺ and 405.1931 (M+H)⁺

EXAMPLE 483-(4-Morpholin-4-ylmethyl-4H-pyrrol-2-ylmethylene)-5-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-1,3-dihydro-indol-2-onehydrochloride Step A: 2-[2-(4-Nitro-phenyl)-ethylamino]-ethanol

A mixture of 1-(2-bromo-ethyl)-4-nitro-benzene (86.9 mmoles) and2-amino-ethanol (869 mmoles) is heated at 150° C. under microwaveactivation for 10 minutes. The reaction mixture is evaporated to drynessand the residue obtained is purified on silica gel (SiO₂; gradientDCM/MeOH) to yield the title product, which is used directly in the nextStep.

Step B: 3-[2-(4-Nitro-phenyl)-ethyl]-oxazolidin-2-one

CDI (89 mmoles) is added to a solution of the compound obtained in StepA (44.5 mmoles) and DMAP (44.5 mmoles) in DCM (250 ml). After stirringfor 4 hours at ambient temperature, the reaction mixture is diluted with300 ml of DCM and then washed with 2M HCl solution (5×200 ml). Theorganic phase is dried over magnesium sulphate, filtered and evaporatedto dryness to yield the title product in the form of an orange solid,which is used directly in the next Step.

Step C: 3-[2-(4-Amino-phenyl)-ethyl]-oxazolidin-2-one

Pd/C 10% (500 mg) is added to a solution of the compound obtained inStep B (16.6 mmoles) in MeOH (100 ml). The reaction mixture is stirredat 50° C. under 4.5 bars of hydrogen for 4 hours. The catalyst isfiltered off and then washed with MeOH. The filtrate is evaporated todryness and the product obtained is triturated in 10 ml of MeOH. Thesolid obtained is filtered off and dried in vacuo at 40° C. overnight toyield the title product in the form of a white solid, which is useddirectly in the next Step.

Step D:2-Hydroxyimino-N-{4-[2-(2-oxo-oxazolidin-3-yl)ethyl]phenyl}acetamide

Sodium sulphate (78.3 g) is added to a solution of trichloroacetaldehydehydrate (32.5 mmoles) in water (100 ml). To the resulting suspensionthere are added a solution of3-[2-(4-amino-phenyl)ethyl]oxazolidin-2-one in water (20 ml) andconcentrated HCl solution (2.83 ml). A solution of hydroxylaminehydrochloride (95 mmoles) in water (50 ml) is then added. The reactionmixture is heated at reflux for two hours. The mixture is then cooled toambient temperature. The solid formed is then filtered off, washed withwater and dried in vacuo in the presence of P₂O₅ and at 40° C. overnightto yield the title product, which is used directly in the next Step.

Step E: 5-[2-(2-Oxo-oxazolidin-3-yl)-ethyl]-1H-indole-2,3-dione

Concentrated H₂SO₄ (20 ml) is heated to 50° C. The compound obtained inStep D (25.24 mmoles) is added slowly in solid form, maintaining thetemperature between 60 and 70° C. The reaction mixture is then stirredfor one hour at 80° C. The mixture is brought to ambient temperature andthen poured onto 200 g of crushed ice. After 30 minutes, the red solidformed is filtered off and washed intensively with ice-cold water; it isthen dried in vacuo in the presence of P₂O₅ and at 40° C. overnight toyield the title product, which is used directly in the next Step.

Step F: 5-[2-(2-oxo-oxazolidin-3-yl)ethyl]-1,3-dihydro-indol-2-one

To a solution of the compound obtained in Step E (7.68 mmoles) in aceticacid (15 ml) there are added TFA (7 ml) and Pd/C 10% (400 mg). Thereaction mixture is stirred at 50° C. under 4 bars of hydrogenovernight. The catalyst is filtered off on a bed of Celite and is thenwashed with acetic acid (20 ml). The filtrate is evaporated to drynessand the residual acetic acid is removed by azeotropic distillation withtoluene. The solid obtained is recrystallised from a mixture ofEtOH/ethyl ether to yield the title product after drying in vacuo.

Mass spectrometry (ES+, m/z): 247.1078 (M+H)⁺

Step G:3-(4-Morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-5-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step F (1.62mmoles) and the compound obtained in Preparation 1 (1.86 mmoles) in thepresence of piperidine in ethanol at reflux. The product obtained afterfiltration is converted into the hydrochloride as described in Step E ofExample 19 to yield the title product. Z isomer.

Mass spectrometry (ES+, m/z): 423.2031 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 60.19 5.93 12.21 7.72 Experimental % 60.21 5.7712.09 8.17

EXAMPLE 493-[4-((1R,5S)-3-Aza-bicyclo[3.1.0]hex-3-ylmethyl)-1H-pyrrol-2-yl-methylene]-5-[2-(2-oxo-oxazolidin-3-yl)ethyl]-1,3-dihydro-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-[2-(2-oxo-oxazolidin-3-yl)ethyl]-1,3-dihydro-indol-2-one (1 mmole) andthe compound obtained in Preparation 4 (1.15 mmoles) in the presence ofpiperidine in ethanol at reflux. The product obtained after filtrationis converted into the hydrochloride as described in Step E of Example 19to yield the title product. Z isomer.

Mass spectrometry (ES+, m/z): 419.2088 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 63.36 5.98 12.32 7.79 Experimental % 63.40 5.7812.22 8.16

EXAMPLE 503-[(6-Fluoro-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dioneStep A: 5-(2-Chloroacetyl)-6-fluoroindolin-2-one

20 mL of DCM are added dropwise under nitrogen to aluminium chloride(31.1 mmol) at 0-5° C. 6-Fluoroindolin-2-one (5.18 mmol) and acetylchloride (6.73 mmol) are added to the mixture. The reaction mixture isheated at 50° C. overnight. The reaction mixture is cooled to ambienttemperature and then poured into an ice bath, and the suspensionobtained is filtered and then washed with cold water to yield the titleproduct.

Step B: Methyl 6-fluoro-2-oxoindoline-5-carboxylate

A solution of the compound obtained in Step A (3.24 mmoles) in pyridine(99 mmol) is stirred at 90° C. for 2 hours. The reaction mixture iscooled to ambient temperature and then filtered. The solid obtained iswashed with ethanol and dried in vacuo at 50° C. The compound isdissolved in MeOH (80 mL), and 0.434 mmol of potassium carbonate isadded. The mixture is stirred at 80° C. for 5 hours. After cooling toambient temperature, 4M HCl/dioxane solution is added (pH 3) and themixture is evaporated to dryness. The residue obtained is triturated inwater, filtered, washed with water and then dried in vacuo at 50° C. toyield the title product.

Step C: 6-Fluoro-5-(hydroxymethyl)indolin-2-one

A solution of the compound obtained in Step B (2.68 mmoles) in anhydrousTHF (20 mL) is maintained under nitrogen in the presence of 0.3 mL ofEtOH. The solution is cooled to 0° C. and then 5.28 mmol of LiBH₄ areadded. The reaction mixture is stirred for 2 hours at ambienttemperature; a second portion of LiBH₄ (6.20 mmol) is then added andstirring is maintained for a further 3 hours. EtOH (0.3 mL) and a thirdportion of LiBH₄ (9.14 mmol) are added and the reaction mixture isstirred overnight. The reaction mixture is quenched with 10 mL of water,and then saturated aqueous NH₄Cl solution (30 mL) is added. Extractionwith EtOAc is carried out, and the organic phases are dried over Na₂SO₄,filtered and evaporated in vacuo. The residue obtained is purified byflash chromatography (DCM/MeOH 10:1) to yield the title product.

Step D:6-Fluoro-5-(hydroxymethyl)-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-1,3-dihydro-2H-indol-2-one

Morpholine (0.662 mmol) and the compound obtained in Preparation 1(0.696 mmol) are added to the compound obtained in Step C (10.662 mmol),dissolved in EtOH (3 ml), and the mixture is heated at reflux for 2hours. The mixture is cooled using an ice bath, and the solidprecipitate formed is filtered off, washed with cold EtOH, thenre-suspended in toluene and evaporated in vacuo (3 times). The residueobtained is dried in vacuo at 40° C. for 4 hours to yield the titleproduct.

Step E:3-[(6-Fluoro-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione

Thiazolidine-2,4-dione (0.350 mmol) and triphenylphosphine on resin(1.66 mmol/g, 0.415 mmol) are stirred for 10 min. at ambient temperaturein anhydrous THF (9 ml) under nitrogen. The mixture is cooled in an icebath and di-tert-butyl azodicarboxylate (0.369 mmol) is added all atonce. The mixture is stirred at 0° C. for 10 min, and then the compoundobtained in Step D (0.238 mmol) is added all at once. The mixture isstirred at 0° C. for 1.5 hours, and then thiazolidine-2,4-dione (0.350mmol), three portions of triphenylphosphine on resin (1.66 mmol/g; 0.166mmol, 0.415 mmol and 0.166 mmol) and three portions of tert-butylazodicarboxylate (each portion 0.369 mmol) are added over a period of 48hours. Silica gel is added and the mixture is evaporated in vacuo. Theresidue obtained is purified by flash chromatography (DCM/MeOH 100:0 to95:5) to yield a dark yellow solid which, after trituration in CH₃CN,yields the title product in the form of a yellow solid.

Melting point: 224-226° C.

EXAMPLE 513-[(7-Fluoro-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione

The procedure is as in Steps A to E of Example 50, replacing the6-fluoroindolin-2-one in Step A by 7-fluoroindolin-2-one. The titleproduct is obtained in the form of a yellow solid.

Melting point: 246-248° C.

EXAMPLE 523-[(4-Fluoro-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione

The procedure is as in Steps A to E of Example 50, replacing the6-fluoroindolin-2-one in Step A by 4-fluoroindolin-2-one. The titleproduct is obtained in the form of a yellow solid.

Melting point: 248-250° C.

EXAMPLE 533-({4-[2-(4-Morpholinyl)ethyl]-1H-pyrrol-2-yl}methylene)-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one and the compoundobtained in Preparation 19.

Melting point: 174° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 60.19 5.93 12.21 7.72 Experimental % 59.47 5.9811.62 7.16

EXAMPLE 543-[(3-{[5-(Morpholin-4-ylmethyl)-1H-pyrrol-3-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dionehydrochloride Step A:5-(Hydroxymethyl)-3-{[5-(morpholin-4-ylmethyl)-1H-pyrrol-3-yl]methylene}-1,3-dihydro-2H-indol-2-one

The title compound is obtained by condensation of the compound obtainedin Step C of Example 1 and the product of Preparation 16 under theconditions described in Step D of Example 1. Mixture of Z/E isomers(46/54).

Mass spectrometry (ES+, m/z): 340.1645 (M+H) and 340.1665 (M+H)

Step B:3-[(3-{[5-(Morpholin-4-ylmethyl)-1H-pyrrol-3-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dionehydrochloride

The title product is obtained by condensation of the product obtained inStep A and thiazolidine-2,4-dione under the conditions described in StepE of Example 1. Mixture of Z/E isomers (47/53)

Mass spectrometry (ES+, m/z): 439.1447 (M+H)⁺ and 439.1425 (M+H)⁺

Elemental Microanalysis:

C H N S Cl Theoretical % 55.63 4.88 11.80 6.75 7.46 Experimental % 56.174.89 12.62 5.92 7.84

EXAMPLE 553-{[3-({5-[(1R,5S)-3-Azabicyclo[3.1.0]hex-3-ylmethyl]-1H-pyrrol-3-yl}-methylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]methyl}4,3-thiazolidine-2,4-dionehydrochloride Step A:3-({5-[(1R,5S)-3-Azabicyclo[3.1.0]hex-3-ylmethyl]-1H-pyrrol-3-yl}methylene)-5-(hydroxy-methyl)-1,3-dihydro-2H-indol-2-one

The title compound is obtained by condensation of the compound obtainedin Step C of Example 1 and the compound obtained in Preparation 17 underthe conditions described in Step D of Example 1. Mixture of Z/E isomers(46/54)

Mass spectrometry (ES+, m/z): 340.1645 (M+H) and 340.1665 (M+H)

Step B:3-{[3-({5-[(1R,5S)-3-Azabicyclo[3.1.0]hex-3-ylmethyl]-1H-pyrrol-3-yl}-methylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]methyl}-1,3-thiazolidine-2,4-dionehydrochloride

The title product is obtained by condensation of the product obtained inStep A and thiazolidine-2,4-dione under the conditions described in StepE of Example 1. Mixture of Z/E isomers (60/40)

Mass spectrometry (ES+, m/z): 435.1487 (M+H)⁺ and 435.1504 (M+H)⁺

EXAMPLE 563-({4-[(1R,5S)-3-Azabicyclo[3.1.0]hex-3-ylmethyl]-1H-pyrrol-2-yl}-methylene)-6-fluoro-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride Step A: 1-(Bromomethyl)-2-fluoro-4-nitrobenzene

To a solution of 2-fluoro-1-methyl-4-nitrobenzene (0.152 mole) intoluene, at reflux, there are added dropwise, over 5 hours, 5.1 ml ofdi-bromine. The reaction mixture is subjected to fractionaldistillation. The residue obtained is triturated in cyclohexane to yieldthe title product in the form of crystals. The title product is useddirectly in the next Step.

Step B: 3-(2-Fluoro-4-nitrobenzyl)-1,3-oxazolidin-2-one

To a suspension of sodium hydride 60% in oil (4.48 mmoles) in a mixtureof THF/DMF (2.7 ml/0.45 ml) at 0° C. under an inert atmosphere there isadded, dropwise, a solution of 1,3-oxazolidin-2-one (24.1 mmoles) in amixture of THF/DMF (71 ml/5.6 ml) over 30 minutes. After stiffing for 1hour, a solution of the compound obtained in Step A (26.5 mmoles) in amixture of THF/DMF (56 ml/11.2 ml) is added over 1.5 hours, maintainingthe temperature below 10° C. Stirring is maintained for 1.5 hours. Water(12 ml) is slowly added to the reaction mixture and then the THF isremoved under reduced pressure. The reaction mixture is diluted withsaturated aqueous NaCl solution and then extracted 3 times with 100 mlof AcOEt. The organic phases are combined, washed with saturated aqueousNaCl solution and then dried with MgSO₄. After filtration, the organicphase is evaporated to dryness. The residue is purified on silica gel(SiO₂, eluant CH₂Cl₂) to yield the title product which is used directlyin the next Step.

Step C: 3-(4-Amino-2-fluorobenzyl)-1,3-oxazolidin-2-one

To a solution of the compound obtained in Step B (10.37 mmoles) inethanol (25 ml) there are added 122 microliters of acetic acid. Thesolution is heated at reflux and stirred for 10 minutes. Powdered iron(2.08 g) and 75 mg of FeCl₃.6H₂O are added. After stiffing for 2 hoursat reflux, the mixture is brought to ambient temperature and thenconcentrated to dryness. 50 ml of water are added to the residueobtained, and the pH is made alkaline using sodium hydroxide. Thesolution is extracted 4 times with AcOEt. The organic phases arecombined and washed with saturated aqueous NaCl solution and then driedwith MgSO₄. After filtration, the organic phase is evaporated to drynessto yield the title product, which is used directly in the next Step.

Step D:6-Fluoro-3-(methylsulphanyl)-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-oneand4-fluoro-3-(methylsulphanyl)-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one

The title products are obtained following the protocol described in StepC of Example 19, using 3-(4-amino-2-fluorobenzyl)-1,3-oxazolidin-2-oneas starting material, and are separated on silica gel (SiO₂, gradientheptane/AcOEt). The title products are used directly in the next Step.

Step E:6-Fluoro-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one

The6-fluoro-3-(methylsulphanyl)-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-oneobtained in Step D is treated as described in Step D of Example 19 toyield the title product.

Mass spectrometry, (ES+, m/z): 251.0834 (M+H)⁺

Step F:3-({4-[(1R,5S)-3-Azabicyclo[3.1.0]hex-3-ylmethyl]-1H-pyrrol-2-yl}methylene)-6-fluoro-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride

The title product is obtained as in Step E of Example 19, using thecompound obtained in Step E and the compound obtained in Preparation 4.Mixture of Z/E isomers (93/7)

Mass spectrometry (ES+, m/z): 423.1817 (M+H)⁺ and 423.1838 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 60.20 5.27 12.21 7.73 Experimental % 59.84 4.8611.76 7.20

EXAMPLE 576-Fluoro-3-{[4-(morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylene}-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-21′-indol-2-onehydrochloride

The title product is obtained as in Step E of Example 19, using thecompound obtained in Step D of Example 56 and the compound obtained inPreparation 1. Mixture of Z/E isomers (95/5)

Mass spectrometry (ES+, m/z): 427.1784 (M+H)⁺ and 427.1795 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 57.08 5.23 12.10 7.66 Experimental % 57.08 4.7211.77 8.13

EXAMPLE 584-Fluoro-3-{[4-(morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylene}-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride Step A:4-Fluoro-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-4,3-dihydro-2H-indol-2-one

The4-fluoro-3-(methylsulphanyl)-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-oneobtained in Step D of Example 56 is treated as described in Step D ofExample 19 to yield the title product.

Mass spectrometry (ES+, m/z): 251.0831 (M+H)⁺

Step B:4-Fluoro-3-{[4-(morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylene}-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride

The title product is obtained as in Step E of Example 19, using thecompound obtained in Step A and the compound obtained in Preparation 1.Mixture of Z/E isomers (97.4/2.6)

Mass spectrometry (ES+, m/z): 427.1781 (M+H)⁺ and 427.1785 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 57.08 5.23 12.10 7.66 Experimental % 57.36 4.4811.88 8.03

EXAMPLE 593-({4-[(1R,5S)-3-Azabicyclo[3.1.0]hex-3-ylmethyl]-1H-pyrrol-2-yl}-methylene)-4-fluoro-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride

The title product is obtained as in Step E of Example 19, using thecompound obtained in Step A and the compound obtained in Preparation 4.Mixture of Z/E isomers (98.5/1.5)

Mass spectrometry (ES+, m/z): 423.1827 (M+H)⁺ and 423.1840 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 60.20 5.27 12.21 7.73 Experimental % 59.61 5.0511.73 7.32

EXAMPLE 603-[(3-{[3-(Morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dionehydrochloride Step A:5-(Hydroxymethyl)-3-{[3-(morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylene}-1,3-dihydro-2H-indol-2-one

The title product is obtained by condensation of the product obtained inStep C of Example 1 and the product obtained in Preparation 8, using theconditions described in Step D of Example 1. Mixture of Z/E isomers(96/4)

Mass spectrometry (ES+, m/z): 340.1652 (M+H)⁺ and 340.1638 (M+H)⁺

Step B:3-[(3-{[3-(Morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dionehydrochloride

The title product is obtained as described in Step E of Example 1,starting from the product obtained in Step A. Mixture of Z/E isomers(96/4)

Mass spectrometry, (ES+, m/z): 423.1827 (M+H)⁺ and 423.1840 (M+H)⁺

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 55.63 4.88 11.80 7.46 Experimental % 56.06 4.5912.03 7.05

EXAMPLE 613-({5-[(3aR,6aS)-Hexahydrocyclopenta[c]pyrrol-2(1H)-ylmethyl]-1H-pyrrol-2-yl}methylene)-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride

The procedure is as in Step E of Example 19, replacing the product ofPreparation 1 by the product of Preparation 20. Mixture of Z/E isomers(98/2)

Mass spectrometry (ES+, m/z): 433.2227 (M+H)⁺ and 433.2234 (M+H)⁺

EXAMPLE 623-{[3-({4-[(4-Methoxypiperidin-1-yl)methyl]-1H-pyrrol-2-yl}methylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]methyl}-1,3-thiazolidine-2,4-dioneStep A:5-(Hydroxymethyl)-3-({4-[(4-methoxypiperidin-1-yl)methyl]-1H-pyrrol-2-yl}methylene)-1,3-dihydro-21′-indol-2-one

The procedure is as in Step D of Example 1, replacing the product ofPreparation 1 by the product of Preparation 21. The title product isused directly in the next Step.

Step B:3-{[3-({4-[(4-Methoxypiperidin-1-yl)methyl]-1H-pyrrol-2-yl}methylidene)-2-oxo-2,3-dihydro-1H-indol-5-yl]methyl}-1,3-thiazolidine-2,4-dione

The procedure is as in Step E of Example 1, replacing the product ofStep D of Example 1 by the product of Step A. In this case, the productobtained is not converted into the hydrochloride. Mixture of Z/E isomers(92.5/7.5)

Mass spectrometry (ES+, m/z): 467.1741 (M+H)⁺ and 467.1742 (M+H)⁺

Elemental Microanalysis:

C H N S⁻ Theoretical % 61.79 5.62 12.01 6.87 Experimental % 61.05 5.6011.64 6.69

EXAMPLE 635-[(2-Oxo-1,3-oxazolidin-3-yl)methyl]-3-({4-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrrol-2-yl}methylene)-1,3-dihydro-2H-indol-2-one

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step D ofExample 19 and the compound obtained in Preparation 18.

Mass spectrometry (ES+, m/z): 407.2088 (M+H)⁺

EXAMPLE 643-{[4-(Morpholin-4-ylmethyl)-1H-pyrrol-3-yl]methylene}-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-1,3-dihydro-2H-indol-2-onehydrochloride

The title product is obtained following the protocol described in Step Eof Example 19 by condensation of the compound obtained in Step D ofExample 19 and the compound obtained in Preparation 22. Mixture of Z/Eisomers (96.7/5.3)

Mass spectrometry (ES+, m/z): 409.1871 (M+H)⁺

Melting point: 210° C.

Elemental Microanalysis:

C H N Cl⁻ Theoretical % 59.39 5.66 12.59 7.97 Experimental % 58.89 5.4512.48 7.79

EXAMPLE 653-[2-(3-{[4-(Morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-4H-indol-5-yl)ethyl]-1,3-thiazolidine-2,4-dionehydrochloride Step A: Ethyl[3-(methylsulphanyl)-2-oxo-2,3-dihydro-1H-indol-5-yl]acetate

The title product is obtained as described in Step A of Example 1,starting from ethyl (4-aminophenyl)acetate, and the product obtained isused directly in the next Step.

Step B: Ethyl (2-oxo-2,3-dihydro-1H-indol-5-yl)acetate

The title product is obtained as described in Step B of Example 1. Theproduct obtained is used directly in the next Step.

Step C: 5-(2-Hydroxyethyl)-1,3-dihydro-2H-indol-2-one

LiBr (1.03 g) is added to a solution of NaBH₄ (0.45 g) in THF (15 ml).The reaction mixture is heated at reflux for 7 hours, and the compoundobtained in Step B (1.3 g) is added, followed by B(OMe)₃ (0.067 ml).After refluxing for 18 hours, the mixture is concentrated under reducedpressure and the residue obtained is taken up in 20 ml of 3NH₂SO₄. Theaqueous phase is saturated with NaCl and extracted with ethyl acetate.The organic phase is dried over magnesium sulphate, filtered andevaporated to dryness. The residue is purified on silica gel (SiO₂,eluant: AcOEt) to yield the title product in the form of a beige solid.The compound obtained is used directly in the next reaction.

Step D:5-(2-Hydroxyethyl)-3-{[4-(morpholin-4-ylmethyl)-1H-pyrrol-2-]-methylene}-1,3-dihydro-2H-indol-2-one

The title product is obtained as in Step D of Example 1, using theproduct obtained in Step C and the compound of Preparation 1. Theproduct obtained is used directly in the next reaction.

Step E:3-[2-(3-{[4-(Morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl]-1,3-thiazolidine-2,4-dionehydrochloride

The title product is obtained as described in Step E of Example 1,starting from the compound obtained in Step D.

Mass spectrometry (ES+, m/z): 453.1612 (M+H)⁺

Melting point: 289° C. decomposition.

Elemental Microanalysis:

C H N S Cl⁻ Theoretical % 56.49 5.15 11.46 6.56 7.25 Experimental %55.74 5.02 11.04 6.13 6.96

EXAMPLE 663-{[3-({4-[(2-Methyl-4-morpholinyl)methyl]-4H-pyrrol-2-yl}methylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]methyl}-1,3-thiazolidine-2,4-dionehydrochloride Step A:5-(Hydroxymethyl)-3-({4-[(2-methyl-4-morpholinyl)methyl]-4H-pyrrol-2-yl}methylene)-1,3-dihydro-2H-indol-2-one

The title product is obtained by condensation of the compound obtainedin Step C of Example 1 and the product obtained in Preparation 23, underthe conditions described in Step D of Example 1.

Step B:3-{[3-({4-[(2-Methyl-4-morpholinyl)methyl]-1H-pyrrol-2-yl}methylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]methyl}-4,3-thiazolidine-2,4-dionehydrochloride

The title product is obtained by condensation of the product obtained inStep A and thiazolidine-2,4-dione, under the conditions described inStep E of Example 1. Mixture of Z/E isomers (95/5)

Mass spectrometry (ES+, m/z): 354.1807 (M+H)⁺ and 354.1803 (M+H)⁺

Elemental Microanalysis:

C H N S % théorique 61.05 5.35 12.38 7.09 % expérimental 60.54 5.3712.13 7.20

PHARMACOLOGICAL STUDY

The compounds of the invention are powerful inhibitors of the migrationof cancerous cells, without non-specific toxicity. By way of example,the results of studying A549 non-small cell lung carcinoma cells arereported hereinbelow.

EXAMPLE A Inhibition of the Migration of A549 Cells: “Scratch Assay”

Cells from the A549 (human non-small cell lung carcinoma) line arecultured in an incubator at 37° C. in the presence of 5% CO₂ in RPMI1640 medium containing 10% foetal calf serum, 40 ng/ml HGF (hepatocytegrowth factor), 2 mM glutamine, 50 units/ml penicillin, 50 μg/mlstreptomycin and 10 mM Hepes buffer, pH=7.4.

For the migration test, the A549 cells are transferred to 96-well plates(50,000 cells per well) and cultured for 24 hours to obtain cells atconfluence. A one-millimeter thick scratch is made in the cell layer,and the cells are exposed to the compounds under test for 38 hours. Thecell cultures are then photographed, and filling of the scratch as aresult of migration of the cells is assessed.

The results show that the compounds of the invention are powerfulinhibitors of cell migration. By way of example, the compound of Example1 shows total inhibition of migration at 30 nM.

EXAMPLE B Absence of Non-Specific Toxicity

In order to show the absence of non-specific toxicity, the A549 cellsare transferred to 96-well plates and exposed to the compounds undertest for 96 hours. Cell viability is then quantified by a colorimetrictest, the Microculture Tetrazolium Assay (Cancer Res., 1987, 47,939-942).

The results show that the compounds of the invention are not toxic toA549 cells at concentrations ranging up to 100 μM.

The compounds of the invention therefore have excellent anti-migratoryactivity without non-specific toxicity.

EXAMPLE C Inhibition of Growth of the Tumour U87-MG

The human glioblastoma tumour U87-MG was grafted subcutaneously into thefemale Nude BalbC mouse in an amount of 10⁶ cells. The tumours were thenrandomised into groups of eight mice once the tumour volume had reached200 mm³. Daily treatment (6.25, 12.5, 25 and 50 mg/kg) was administeredby the oral route (vehicle=water) over a period of 17 days except forthe weekends. The tumour volumes were measured twice a week using asliding calliper. The inhibition of growth found after administration ofthe compounds according to the invention is statistically significant(two-factor ANOVA, with measurements repeated over time, followed by aDUNETT's test) at all doses tested between Day 21 and Day 35 (date forethical sacrifice of the mice in the control group in conformity withethical rules). Accordingly, by way of example, the compound of Example1, on Day 35, makes it possible to obtain inhibition of growth of 102%,84% and 98% for doses of 6.25 mg/kg, 12.5 mg/kg and 25 mg/kg,respectively. Regression of the order of 70% is observed at a dose of 50mg/kg.

EXAMPLE D Pharmaceutical Composition: Tablets

1000 tablets each containing 5 mg of3-[3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]-methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione

hydrochloride (Example 1) . . . 5 g

Wheat starch . . . 20 g

Maize starch . . . 20 g

Lactose . . . 30 g

Magnesium stearate . . . 2 g

Silica . . . 1 g

Hydroxypropylcellulose . . . 2 g

The invention claimed is:
 1. A method of treating metastatic cancers ina subject in need thereof comprising administration of an effectiveamount of a compound selected from those of formula (I):

wherein: m represents 1 or 2, n represents 1 or 2, A represents apyrrolyl group which is unsubstituted or substituted by 1 to 3 linear orbranched (C₁-C₆)alkyl groups, X represents a C(O), S(O) or SO₂ group, R₁and R₂, which are the same or different, each represent a linear orbranched (C₁-C₆)alkyl group, or R₁ and R₂, together with the nitrogenatom carrying them, form a heterocyclic group, R₃ and R₄, together withthe atoms carrying them, form a heterocyclic group, R₅ represents ahydrogen atom or a linear or branched (C₁-C₆)alkyl group, R₆ representsa hydrogen atom or a halogen atom, it being understood that: a“heterocyclic group” means a mono- or bi-cyclic group which may containfrom 5 to 8 members, which may contain from one to three hetero atomsselected from nitrogen, oxygen and sulphur, and which may contain one ormore unsaturated bonds, wherein the heterocyclic group is optionallysubstituted by one or more groups selected from linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkenyl, oxo, hydroxy, linear orbranched (C₁-C₆)alkoxy, aryl, arylalkyl and arylalkenyl, “aryl” means aphenyl group which is optionally substituted by one or more groupsselected from halogen atoms and linear or branched (C₁-C₆)alkyl groups,the notation

representing the exocyclic double bond at the 3-position of the indolonering means that the double bond is of configuration Z or E, its opticaland geometric isomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 2. The method of claim 1,wherein R₁ and R₂, together with the nitrogen atom carrying them, form amorpholinyl group, m and n have the value 1, R₅ and R₆ represent ahydrogen atom and A represents a 1H-pyrrol-2,4-yl group.
 3. The methodof claim 1, wherein the compound of formula (I) is3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione,or an optical or geometric isomer, or addition salt thereof with apharmaceutically acceptable acid or base.
 4. The method of claim 1,wherein the compound of formula (I) is3-[((3Z)-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione,or an addition salt thereof with a pharmaceutically acceptable acid orbase.
 5. A method of inhibiting the migration of cancerous cells in asubject in need thereof comprising administration of an effective amountof a compound selected from those of formula (I):

wherein: m represents 1 or 2, n represents 1 or 2, A represents apyrrolyl group which is unsubstituted or substituted by 1 to 3 linear orbranched (C₁-C₆)alkyl groups, X represents a C(O), S(O) or SO₂ group, R₁and R₂, which are the same or different, each represent a linear orbranched (C₁-C₆)alkyl group, or R₁ and R₂, together with the nitrogenatom carrying them, form a heterocyclic group, R₃ and R₄, together withthe atoms carrying them, form a heterocyclic group, R₅ represents ahydrogen atom or a linear or branched (C₁-C₆)alkyl group, R₆ representsa hydrogen atom or a halogen atom, it being understood that: a“heterocyclic group” means a mono- or bi-cyclic group which may containfrom 5 to 8 members, which may contain from one to three hetero atomsselected from nitrogen, oxygen and sulphur, and which may contain one ormore unsaturated bonds, wherein the heterocyclic group is optionallysubstituted by one or more groups selected from linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkenyl, oxo, hydroxy, linear orbranched (C₁-C₆)alkoxy, aryl, arylalkyl and arylalkenyl, “aryl” means aphenyl group which is optionally substituted by one or more groupsselected from halogen atoms and linear or branched (C₁-C₆)alkyl groups,the notation

representing the exocyclic double bond at the 3-position of the indolonering means that the double bond is of configuration Z or E, its opticaland geometric isomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 6. The method of claim 5,wherein R₁ and R₂, together with the nitrogen atom carrying them, form amorpholinyl group, m and n have the value 1, R₅ and R₆ represent ahydrogen atom and A represents a 1H-pyrrol-2,4-yl group.
 7. The methodof claim 5, wherein the compound of formula (I) is3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione,or an optical or geometric isomer, or addition salt thereof with apharmaceutically acceptable acid or base.
 8. The method of claim 5,wherein the compound of formula (I) is3-[((3Z)-3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione,or an addition salt thereof with a pharmaceutically acceptable acid orbase.